WO1997010002A1 - Immunotherapy of cancer and infectious disease using antigen-presenting cells sensitized with heat shock protein-antigen complexes - Google Patents

Immunotherapy of cancer and infectious disease using antigen-presenting cells sensitized with heat shock protein-antigen complexes Download PDF

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Publication number
WO1997010002A1
WO1997010002A1 PCT/US1996/014558 US9614558W WO9710002A1 WO 1997010002 A1 WO1997010002 A1 WO 1997010002A1 US 9614558 W US9614558 W US 9614558W WO 9710002 A1 WO9710002 A1 WO 9710002A1
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cells
presenting cells
antigen presenting
cancer
human
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PCT/US1996/014558
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English (en)
French (fr)
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Pramod K. Srivastava
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Fordham University
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Fordham University
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Priority to DK96930819T priority Critical patent/DK0857068T3/da
Priority to JP9512064A priority patent/JPH11512433A/ja
Priority to CA002232002A priority patent/CA2232002A1/en
Priority to AU69735/96A priority patent/AU728929B2/en
Priority to DE69632261T priority patent/DE69632261T2/de
Priority to EP96930819A priority patent/EP0857068B1/en
Priority to AT96930819T priority patent/ATE264910T1/de
Publication of WO1997010002A1 publication Critical patent/WO1997010002A1/en
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/191—Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/10—Cellular immunotherapy characterised by the cell type used
    • A61K40/17—Monocytes; Macrophages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/20—Cellular immunotherapy characterised by the effect or the function of the cells
    • A61K40/24—Antigen-presenting cells [APC]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
    • A61K40/41—Vertebrate antigens
    • A61K40/42—Cancer antigens
    • A61K40/4262—Heat shock proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6031—Proteins
    • A61K2039/6043—Heat shock proteins
    • 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
    • A61K2039/62—Medicinal preparations containing antigens or antibodies characterised by the link between antigen and carrier
    • A61K2039/622—Medicinal preparations containing antigens or antibodies characterised by the link between antigen and carrier non-covalent binding
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterized by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the cancer treated
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to compositions and methods of adoptive immunotherapy for the prevention and/or treatment of primary and metastatic cancer and other immunological or infectious disorders in humans using macrophages sensitized with non-covalent complexes of heat
  • shock protein hsp
  • antigenic molecules 15 shock protein (hsp) and antigenic molecules.
  • compositions of hsp including, but not limited to, hsp70, hsp90, gp96 alone or in combination with each other, non ⁇ covalently bound to antigenic molecules, are used to
  • 25 including, but not limited to, hsp70, hsp90, gp96 alone or in combination with each other, are used to augment the immune response to genotoxic and nongenotoxic factors, tumors and infection.
  • Adoptive immunotherapy of cancer refers to a therapeutic approach in which immune cells with an antitumor reactivity are administered to a tumor-bearing host, with the aim that the cells mediate either directly or indirectly, the
  • the toxicity of the high-dose IL-2 + activated lymphocyte treatment advocated by the NCI group has been considerable, including high fevers, 5 severe rigors, hypotension, damage to the endothelial wall due to capillary leak syndrome, and various adverse cardiac events such as arrhythmias and myocardial infarction (Rosenberg S.A. , et al., 1988, N. England J. Med . 319:1676- 1680) .
  • Rosenberg S.A. et al., 1988, N. England J. Med . 319:1676- 1680
  • mice with gp96 or p84/86 isolated from a particular tumor rendered the mice immune to that particular tumor, but not to antigenically distinct tumors. Isolation and characterization of genes encoding gp96 and p84/86 revealed significant homology between them, and showed that gp96 and p84/86 were, respectively, the endoplas ic reticular and cytosolic counter parts of the same heat shock proteins (Srivastava, P.K. , et al., 1988, Immunogenetics 28:205-207; Srivastava, P.K. , et al., 1991, Curr. Top. Microbiol . Immunol . 167:109-123).
  • hsp70 was shown to elicit immunity to the tumor from which it was isolated but not to antigenically distinct tumors. However, hsp70 depleted of peptides was found to lose its immunogenic activity (Udono, M., and Srivastava, P.K. , 1993, J. Exp. Med. 178:1391-1396). These observations suggested that the heat shock proteins are not immunogenic per se, but are carriers of antigenic peptides that elicit specific immunity to cancers (Srivastava, P.K. , 1993, Adv. Cancer Res . 62:153-177).
  • macrophages originate in the bone marrow from myeloid stem cells. They circulate in the blood as monocytes and undergo final differentiation to mature tissue macrophages in liver, spleen and lung, among other tissues. Macrophages appear to be major effector cells and leukocytes such as T-lymphocytes and NK cells also play a part in cell- mediated cytotoxicity.
  • hsps heat shock proteins
  • hsp60, hsp70 and hsp90 where the numbers reflect the approximate molecular weight of the stress proteins in kilodaltons. Many members of these families were found subsequently to be induced in response to other stressful stimuli including, but not limited to, nutrient deprivation, metabolic disruption, oxygen radicals, and infection with intracellular pathogens.
  • stressful stimuli including, but not limited to, nutrient deprivation, metabolic disruption, oxygen radicals, and infection with intracellular pathogens.
  • hsps can accumulate to very high levels in stressed cells, but they occur at low to moderate levels in cells that have been stressed.
  • the highly inducible mammalian hsp70 is hardly detectable at normal temperatures but becomes one of the most actively synthesized proteins in the cell upon heat shock (Welch, et al., 1985, J. Cell . Biol . 101:1198-1211).
  • hsp90 and hsp60 proteins are abundant at normal temperatures in most, but not all, mammalian cells and are further induced by heat (Lai, et al., 1984, Mol . Cell . Biol . 4:2802-10; van Bergen en Henegouwen, et al., 1987, Genes Dev. 1:525-31).
  • Heat shock proteins are among the most highly conserved proteins in existence.
  • DnaK the hsp70 from E. 5 coli has about 50% amino acid sequence identity with hsp70 proteins from excoriates (Bardwell, et al., 1984, Proc . Natl . Acad. Sci . 81:848-852).
  • the hsp60 and hsp90 families also show similarly high levels of intra families conservation (Hickey, et al. , 1989, Mol . Cell . Biol . 9:2615-2626; Jindal,
  • hsp60, hsp70 and hsp90 families are composed of proteins that are related to the stress proteins in sequence, for example, having greater than 35% amino acid identity, but whose expression levels are not altered by
  • the hsp-antigenic molecule complexes used to sensitize APCs according to the invention may include any complex 5 containing an hsp and a molecule that is capable of inducing an immune response in a mammal.
  • the antigenic/immunogenic molecules are noncovalently associated with the hsp.
  • Preferred complexes include, but are not limited to, hsp60- peptide, hsp70-peptide and hsp90-peptide complexes, in which 0 the hsp-peptide complex is present in vivo and is isolated from cells.
  • APC are sensitized with hsp complexed with immunogenic or antigenic molecules that are endogenously complexed to hsps or MHC antigens and can be used as antigenic molecules.
  • immunogenic or antigenic molecules that are endogenously complexed to hsps or MHC antigens and can be used as antigenic molecules.
  • such peptides may be prepared that stimulate cytotoxic T cell responses against different tumor specific antigens (e . g .
  • hsps can be purified for such use from the endogenous hsp-peptide complexes in the presence of ATP or low pH (or chemically synthesized or recombinantly produced) .
  • hsp-peptide complexes or the hsps alone, from any eukaryotic cells for example, tissues, isolated cells, or immortalized eukaryote cell lines infected with a preselected intracellular pathogen, tumor cells or tumor cell lines.
  • the column is then developed with a 20mM to 500mM NaCl gradient and then eluted fractions fractionated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and characterized by immunoblotting using an appropriate anti-hsp70 antibody (such as from clone N27F3-4, from StressGen) .
  • an appropriate anti-hsp70 antibody such as from clone N27F3-4, from StressGen
  • the present invention further describes a new and rapid method for purification of hsp70-peptide complexes.
  • This improved method uses chromatography with ADP affixed to a solid substratum (e.g., ADP-agarose) .
  • ADP a solid substratum
  • the resulting hsp70 preparations are higher in purity and devoid of peptides.
  • the hsp70 yields are also increased significantly by about more than 10 fold.
  • chromatography with nonhydrplyzable analogs of ATP instead of ADP, can be used 5 in chromatography for purification of hsp70-peptide complexes.
  • purification of hsp70-peptide complexes by ADP-agarose chromatography was carried out as follows: Meth A sarcoma cells (500 million cells) were homogenized in hypotonic
  • the lysate is centrifuged at l,000g for 10 minutes to remove unbroken cells, nuclei and other cellular debris.
  • the resulting supernatant is recentrifuged at 100,000g for 90 minutes, the supernatant harvested and then mixed with Con A Sepharose equilibrated with PBS containing 2mM Ca 2+ and 2mM Mg 2+ .
  • Con A Sepharose equilibrated with PBS containing 2mM Ca 2+ and 2mM Mg 2+ .
  • the supernatant is diluted with an equal volume of 2X Lysis buffer prior to mixing with Con A Sepharose.
  • the supernatant is then allowed to bind to the Con A Sepharose for 2-3 hours at ⁇ C.
  • the material that fails to bind is harvested and dialyzed for 36 hours (three times, 100 volumes each time) against lOmM Tris-Acetate pH 7.5, O.lmM EDTA, lOmM NaCl, ImM PMSF. Then the dialyzate is centrifuged at 17,000 rpm (Sorvall SS34 rotor) for 20 minutes. Then the resulting supernatant is harvested and applied to a Mono Q FPLC column equilibrated with lysis buffer. The proteins are then eluted with a salt gradient of 200mM to 600mM NaCl.
  • the resulting samples are centrifuged through an Centricon 10 assembly as mentioned previously.
  • the high and low molecular weight fractions are recovered.
  • the remaining large molecular weight stress protein-peptide complexes can be reincubated with ATP or low pH to remove any remaining peptides.
  • 5- fluorouracil are mixed and fewer than 25 percent of patients experience a greater than 50 percent reduction in tumor mass (Richards, 2d., F. , et al., 1986, J. Clin . Oncol . 4:565).
  • cirrhosis that can lead to hepatocellular carcinoma
  • Other causes of cirrhosis that can lead to hepatocellular carcinoma include alcohol abuse and hepatic fibrosis caused by chronic administration of methotrexate.
  • the most frequent symptoms of hepatocellular carcinoma are the development of a painful mass in the right upper quadrant or epigastrium, accompanied by weight loss.
  • the development of hepatocellular carcinoma is preceded by ascites, portal hypertension and relatively abrupt clinical deterioration.
  • abnormal values in standard liver function tests such as serum aminotransferase and alkaline phosphatase are observed.
  • Another specific aspect of the invention relates to the treatment of breast cancer.
  • the American Cancer Society estimated that in 1992 180,000 American women were diagnosed with breast cancer and 46,000 succumbed to the disease (Niederhuber, J.E.ed. Current Therapy in Oncology B.C.
  • the present invention provides hsp compositions and methods for enhancing specific immunity to preneoplastic and neoplastic mammary cells in women.
  • the present invention also provides compositions and methods for preventing the development of neoplastic cells in women at enhanced risk for breast cancer, and for inhibiting cancer cell proliferation and metastasis. These compositions can be applied alone or in combination with each other or with biological response modifiers.
  • antigens Proper technique of skin testing requires that the antigens be stored sterile at 4°C, protected from light and reconstituted shorted before use.
  • a 25- or 27-gauge need ensures intradermal, rather than subcutaneous, administration of antigen. Twenty-four and 48 hours after intradermal administration of the antigen, the largest dimensions of both erythema and induration are measured with a ruler.
  • Peritoneal macrophages (5xl0 6 ) were sensitized with gp96 (10 micrograms/ml) derived from Nl cells, EL4 cells, VSV nucleocapsid K b epitope peptide (10 micro M) as a positive control, or culture medium as control, for 2 hr at 37°C, followed by labeling with s, Cr for 1.5 hr. These sensitized macrophages were used as targets in a 4 hr sl Cr-release assay with VSV-specific CTLs.
  • Anti-CD4 mAb (CK1.5), anti-CD8 mAb (YTS169.4) , anti-H-2K b mAb (Y3), anti-H-2D b mAb (B22.249) or RPMI control were added to the CTL assay at the same time as effector cells and 51 Cr- labeled macrophages sensitized with gp96 from Nl cells.
  • Peritoneal exudate cells or macrophages (4xl0 7 ) were incubated at 37 ⁇ C for 3 hr in 1ml RPMI containing 50 ⁇ g gp96-peptide complexes derived from Methylcholanthrene- induced tumors or from liver. The macrophages were then washed 3 times and resuspended at a concentrate of lxl ⁇ 7 /ml in RPMI medium. 200 microliter of this suspension was used to inject mice intraperitoneally as described in the experimental protocol below. i
  • Tumor growth was comparable in groups A, B and C, i.e. mice receiving the control buffer solution or the gp96 derived from liver tissue.
  • administration of gp96-peptide complexes directly or adoptive therapy with macrophages and/or other APC sensitized with gp96-peptide complexes, described herein represents an approach to treatment of cancer with potential applicability to a wide range of cancers, infectious diseases or immunological disorders.

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PCT/US1996/014558 1995-09-13 1996-09-11 Immunotherapy of cancer and infectious disease using antigen-presenting cells sensitized with heat shock protein-antigen complexes Ceased WO1997010002A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
DK96930819T DK0857068T3 (da) 1995-09-13 1996-09-11 Immunoterapi ved cancer- og infektionssygdom under anvendelse af antigenpræsenterende celler, der er sensibiliseret med varmechok-protein-antigenkomplekser
JP9512064A JPH11512433A (ja) 1995-09-13 1996-09-11 熱ショックタンパク質−抗原複合体で感作した抗原提示細胞を用いる癌及び感染症の免疫療法
CA002232002A CA2232002A1 (en) 1995-09-13 1996-09-11 Immunotherapy of cancer and infectious disease using antigen-presenting cells sensitized with heat shock protein-antigen complexes
AU69735/96A AU728929B2 (en) 1995-09-13 1996-09-11 Immunotherapy of cancer and infectious disease using antigen-presenting cells sensitized with heat shock protein-antigen complexes
DE69632261T DE69632261T2 (de) 1995-09-13 1996-09-11 Krebs und infektiöse krankheiten immuntherapie unter anwendung von antigen -präsentierenden zellen sensibilisiert mit hitzeschock - protein - antigen - komplexen
EP96930819A EP0857068B1 (en) 1995-09-13 1996-09-11 Immunotherapy of cancer and infectious disease using antigen-presenting cells sensitized with heat shock protein-antigen complexes
AT96930819T ATE264910T1 (de) 1995-09-13 1996-09-11 Krebs und infektiöse krankheiten immuntherapie unter anwendung von antigen -präsentierenden zellen sensibilisiert mit hitzeschock - protein - antigen - komplexen

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US08/527,546 US5985270A (en) 1995-09-13 1995-09-13 Adoptive immunotherapy using macrophages sensitized with heat shock protein-epitope complexes
US527,546 1995-09-13

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US (2) US5985270A (enExample)
EP (1) EP0857068B1 (enExample)
JP (1) JPH11512433A (enExample)
AT (1) ATE264910T1 (enExample)
AU (1) AU728929B2 (enExample)
CA (1) CA2232002A1 (enExample)
DE (1) DE69632261T2 (enExample)
DK (1) DK0857068T3 (enExample)
ES (1) ES2219696T3 (enExample)
PT (1) PT857068E (enExample)
WO (1) WO1997010002A1 (enExample)
ZA (1) ZA967756B (enExample)

Cited By (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5948646A (en) * 1997-12-11 1999-09-07 Fordham University Methods for preparation of vaccines against cancer comprising heat shock protein-peptide complexes
WO1999050391A1 (en) * 1998-03-30 1999-10-07 I.D.M. Immuno-Designed Molecules Stimulated monocyte derived cells, their preparation and uses
WO1999053026A1 (en) * 1998-04-09 1999-10-21 I.D.M. Immuno-Designed Molecules Use of monocytes derived cells, antigens and antibodies for optimal induction of immunotherapeutic efficiency
WO2001023421A3 (en) * 1999-09-30 2001-10-25 Corixa Corp Stress protein compositions and methods for prevention and treatment of cancer and infectious disease
US6331299B1 (en) 1995-08-18 2001-12-18 Sloan-Kettering Institute For Cancer Research Method for treatment of cancer and infectious disease and compositions useful in same
WO2001063278A3 (en) * 2000-02-23 2002-03-14 Immunobiology Ltd Antigenic fragments associated with stress-induced proteins and their use as vaccines
EP1209226A3 (en) * 2000-11-07 2002-06-05 GSF-Forschungszentrum für Umwelt und Gesundheit GmbH Maturation of dendritic cells by recombinant heat shock protein 70 (hsp70)
EP1064390A4 (en) * 1998-03-20 2002-06-12 Genzyme Corp Enhanced anti-tumor immunity
US6605464B1 (en) 1995-08-18 2003-08-12 Sloan-Kettering Institute For Cancer Research Method of treatment of cancer and infectious disease and compositions useful in same
JP2003527322A (ja) * 1999-08-19 2003-09-16 イミューノバイオロジー リミティッド 細胞内病原体に対するワクチン
US6719974B1 (en) 1995-08-18 2004-04-13 Sloan-Kettering Institute For Cancer Research Heat shock protein-based vaccines and immunotherapies
US6761892B1 (en) 1995-08-18 2004-07-13 Sloan-Kettering Institute For Cancer Research Heat shock protein-based vaccines and immunotherapies
US6773707B1 (en) 1995-08-18 2004-08-10 Sloan-Kettering Institute For Cancer Research Heat shock protein-based vaccines and immunotherapies
WO2004074454A2 (en) 2003-02-20 2004-09-02 University Of Connecticut Health Center Methods and compositions for the treatment of cancer and infectious disease using alpha (2) macroglobulin-antigenic molecule complexes
US6797480B1 (en) 1998-10-05 2004-09-28 University Of Connecticut Health Center Purification of heat shock/stress protein cell surface receptors and their use as immunotherapeutic agents
WO2005020936A2 (en) 2003-02-28 2005-03-10 Antigenics Inc. Use of lectins to promote oligomerization of glycoproteins and antigenic molecules
EP1030909A4 (en) * 1998-09-11 2005-11-16 Medical Inc Sentron ACTIVATION OF IMMUNE SYSTEM USING BICATENE POLYNUCLEOTIDES
US7014848B1 (en) 1998-03-20 2006-03-21 Genzyme Corporation Enhanced anti-tumor immunity
US7179462B2 (en) 2000-06-02 2007-02-20 University Of Connecticut Health Center α (2) macroglobulin receptor as a heat shock protein receptor and uses thereof
US7186515B1 (en) 2000-06-02 2007-03-06 University Of Connecticut Health Center Alpha(2) macroglobulin receptor as a heat shock protein receptor and uses thereof
EP1829551A1 (en) 1998-02-20 2007-09-05 University Of Miami Modified heat shock protein-antigenic peptide complex
US7309491B2 (en) 2003-04-11 2007-12-18 Antigenics Inc. Heat shock protein-based vaccines and immunotherapies
US7378096B2 (en) 1999-09-30 2008-05-27 Health Research, Inc. Stress protein compositions and methods for prevention and treatment of cancer and infectious disease
US7420037B2 (en) 2003-02-13 2008-09-02 Antigenics Inc. Heat shock protein-based vaccines and immunotherapies
US7449557B2 (en) 2000-06-02 2008-11-11 University Of Connecticut Health Center Complexes of alpha (2) macroglobulin and antigenic molecules for immunotherapy
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PT857068E (pt) 2004-09-30
EP0857068B1 (en) 2004-04-21
CA2232002A1 (en) 1997-03-20
DE69632261T2 (de) 2005-04-14
US5985270A (en) 1999-11-16
ZA967756B (en) 1997-04-16
US6156302A (en) 2000-12-05
JPH11512433A (ja) 1999-10-26
AU6973596A (en) 1997-04-01
DE69632261D1 (de) 2004-05-27
EP0857068A4 (en) 2000-01-19
AU728929B2 (en) 2001-01-18
EP0857068A1 (en) 1998-08-12
ATE264910T1 (de) 2004-05-15
DK0857068T3 (da) 2004-08-16
ES2219696T3 (es) 2004-12-01

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