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WO1987006840A1 - Vaccin stimulant ou ameliorant la production d'anticorps contre le gm2 - Google Patents

Vaccin stimulant ou ameliorant la production d'anticorps contre le gm2 Download PDF

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Publication number
WO1987006840A1
WO1987006840A1 PCT/US1987/001049 US8701049W WO8706840A1 WO 1987006840 A1 WO1987006840 A1 WO 1987006840A1 US 8701049 W US8701049 W US 8701049W WO 8706840 A1 WO8706840 A1 WO 8706840A1
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WIPO (PCT)
Prior art keywords
vaccine
subject
cancer
adjuvant
patients
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PCT/US1987/001049
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English (en)
Inventor
Philip O. Livingston
Lloyd J. Old
Michele Jones Calves
Edward J. Natoli
Herbert F. Oettgen
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Sloan-Kettering Institute For Cancer Research
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Publication of WO1987006840A1 publication Critical patent/WO1987006840A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001169—Tumor associated carbohydrates
    • A61K39/001171—Gangliosides, e.g. GM2, GD2 or GD3
    • 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
    • A61K2039/55588—Adjuvants of undefined constitution
    • A61K2039/55594—Adjuvants of undefined constitution from bacteria

Definitions

  • Gangliosides are prominent cell-surface constituents of melanoma and other tumors of neuroectodermal origin.
  • gangliosides the monosialoganglioside GM2 and the disialogangliosides GD2 and GD3, are of particular interest to tumor immunologists because of their potential as targets for passive immunization with monoclonal antibodies (mAbs) and for active immunization with cancer vaccines.
  • mAbs monoclonal antibodies
  • GD2 and GD3 are immunogenic in mice and humans; mouse mAbs have been generated against GM2 (2), GD2 (3,4), and GD3 (5-8), and human sera and human mAbs with reactivity for GM2 (9-12), GD2 (11, 13, 14) and GD3 (15) have been identified.
  • Livingston, et al. (22, 23) teach BCG and Salmonella useful as adjuvants in stimulating an immunogenic reaction. However, Livingston, et al. neither teach nor suggest the use of such adjuvants to stimulate or enhance antibodies against GM2. Further, Livingston, et al. do not disclose the use of the Salmonella minnesota R595 as an adjuvant. Tai, et al. identified the immunogenicity of GM2 in studies of melanoma patients (12). However Tai, et al. do not teach or suggest the use of BCG or Salmonella minnesota R595 to stimulate or enhance antibodies directed against GM2.
  • Irie, et al. U.S. Patent No. 4,557,931, issued December 10, 1985, disclose the use of GM2 in combination with an adjuvant to raise antibodies against GM2.
  • Irie, et al. use as adjuvants liposomes or serum albumin.
  • Irie, et al. do not teach or suggest the use of BCG or Salmonella minnesota R595 to stimulate or enhance antibodies directed against GM2.
  • This invention provides a vaccine for stimulating or enhancing in a subject to whom the vaccine is administered, production of antibodies directed against GM2.
  • the vaccine comprises an amount of purified GM2 effective to stimulate or enhance antibody production in the subject, an effective amount of a microbial adjuvant and a pharmaceutically acceptable carrier.
  • the microbial adjuvant may be bacillus Calmette-Guerin or Salmonella minnesota R595.
  • This invention also provides a method for stimulating or enhancing in a subject production of antibodies directed against GM2.
  • the method comprises administering to the subject an effective dose of the vaccine of this invention.
  • This invention further provides a method for treating cancer in a subject affected with cancer.
  • the method comprises administering to the subject an effective dose of the vaccine of this invention.
  • this invention provides a method for preventing cancer in a subject affected with cancer.
  • the method comprises administering to the subject an effective dose of the vaccine of this invention.
  • Figure 1 shows the GM2 antibody response of stage III melanoma patients after immunization with a whole-cell vaccine or purified GM2 ganglioside vaccines. Each curve represents the response of an individual patent. Arrows indicate time of Cy injection or vaccine injection.
  • the adjuvant used in the booster vaccine was the same as the adjuvant used in the initial vaccines, except in cases in which BCG was replaced by R595.
  • Figure 2 shows the detection of GM2 antibody in sera from vaccinated melanoma patients by immunostaining.
  • Identical TLC plates were stained with resorcinol (far left) or were allowed to react with patients vaccinated with GM2/BCG: GM2 antibody titers by EL ISA 1:160 and 1:320.
  • D and E sera from two patients treated with Cy and vaccinated with GM2/BCG: GM2 antibody titers by ELISA-1:80 and 1:160.
  • F serum from a patient vaccinated with GM2/R595: GM2 antibody titer by ELISA 1:20.
  • This invention provides a vaccine for stimulating or enhancing in a subj ect to whom the vaccine is administered, production of antibodies directed against GM2 .
  • the vaccine comprises an amount of purif ied GM2 effective to stimulate or enhance antibody production in the subj ect, an effective amount of a microbial adj uvant and a pharmaceutically acceptable carrier.
  • the subj ect is a human being and the GM2 is bound to the microbi al adj uvant by a hydrophobic bond between the l ipid portion of the GM2 and the cell membrane of the microbial adj uvant.
  • the pharmaceutically acceptable carrier may be any well known carrier.
  • the presently pr eferred carrier is a phosphate buffered saline solution.
  • the preferred microbial adj uvant is bacillus CalmetteGuerin.
  • the microbial adj uvant may also be Salmonella minnesota R595.
  • a range of the amount of purif ied GM2 may be emopl oyed.
  • the preferred amount present in the vaccine i s an amount between about 50 micrograms and about 300 micrograms.
  • a range of thee amount of Salmonella minnesota R595 may be empl oyed.
  • the preferred amount present in the vaccine is an amount between about .2 mg and about 1 .5 mg.
  • a range of the amount of bacillus Calmette-Guerin may be empl oyed.
  • the pref erred amount present in the vaccine is an amount between about 10 3 viable uni ts and about 3 x 10 7 viable uni ts.
  • This invention also provides for administering a vaccine of this invention to a subject afflicted with cancer. The antibody produced in the subject upon administration of the vaccine effectively treats the cancer.
  • This invention still further provides for administering a vaccine of this invention to a subject susceptible to cancer .
  • the antibody produced in the subj ect upon administration of the vaccine effectively prevents the cancer.
  • the cancer treated or prevented by the vaccine of this invention may be of neuroectodermal origin.
  • the cancer of neuroectode rmal origin may be a melanoma.
  • This invention also discloses a method for stimulating or enhancing in a subject production of antibodies directed against GM2.
  • the method comprises administering to the subject an effective dose of the vaccine of this invention.
  • This invention further discloses a method for treating cancer in a subject affected with cancer.
  • the method comprises administering to the subject an effective dose of a vaccine of this invention.
  • This invention still further discloses a method for preventing cancer in a subject affected with cancer.
  • the method comprises administering to the subject an effective dose of a vaccine of this invention.
  • the vaccine may be administered subcutaneously, intradermally or intramuscularly. Further, the vaccine may be administered in a single dose or by a single dose followed by a booster dose.
  • the booster dose is preferably administered 12-16 weeks after the inital dose.
  • the methods of this invention employ the GM2 bound to the microbial adjuvant by a hydrophobic bond between the lipid portion of the GM2 and the cell membrane of the microbial adjuvant.
  • the microbial adjuvant may be Salmonella minnesota R595 or bacillus Calmette-Guerin.
  • the methods of treating or preventing cancer may involve a cancer of neuroectodermal origin.
  • the cancer of neuroectodermal origin may be a melanoma.
  • an effective amount of cyclophosphamide may be administered to the subject prior to administering the vaccine.
  • a range of time prior to administering the vaccine may be employed.
  • the perferred time for administering the cyclophosphamide is between about 3 days and about 7 days prior to administering the vaccine.
  • a range of the amount of cyclophosphamide may be employed.
  • the preferred amount is between about 1 mg/m 2 and about 500 mg/m 2 .
  • mice Female BALB/c-C57BL/6 F 1 (B6) mice, 2 to 5 mo of age, were obtained from The Jackson Laboratory, Bar Harbor, ME.
  • Serological assays Mice were bled from the retroorbital sinus at 2 wk intervals after vaccination, and serum samples for serological testing (approximately 0.1 ml) were stored at -20°C.
  • the immune adherence (IA) and complement-dependent cytotoxicity assays (with the use of rabbit complement) that detect primarily immunoglobulin M (IgM) and the protein A (PA), and anti-IgG assays that detect primarily IgG, were performed as described (22, 37, 38).
  • the results of the PA, anti-IgG, and IA assays were analyzed microscopically and were expressed as the highest antibody titer resulting in 20% of the target cells having indicator red cells attached to 50% or more of their cell perimeters.
  • JB-RH preparation of vaccines: vaccine containing JB-RH cells.
  • JB-RH was grown in tissue culture with medium containing 5% fetal calf serum. On the day of vaccination, cells were dislodged mechanically, irradiated with 10,000 rad from a Cobalt 60 source, and counted. Cells (5 x 10 7 ) were mixed with 50 micrograms of MPLA in 0.2 ml normal saline, as described (22). Ganglioside content of this vaccine was determined by extracting the cells as described (2) , performing TLC, and quantitating the gangliosides by densitometric scanning (2). JB-RH cells (5 x 10 7 ) contain 60 micrograms of GM2.
  • Vaccines containing bacteria J-5 E. coli and Salmonella minnesota (American Type Culture collection, Rockville, MD), and Salmonella minnesota mutant R595 (kindly provided by Dr. Jerry McGhee, University of Alabama) were boiled in 1% acetic acid as described (27), were washed, and were stored frozen before use. The day before vaccination, these bacteria or BCG (Tice strain: University of Illinois Medical Center) were resuspended in distilled water by sonication and were added to tubes containing dried GM2. The suspension was lyophilized and on the day of vaccination was resuspended in normal saline shortly before administration.
  • Liposome vaccines Liposome preparation 1 was prepared by mixing 200 micrograms of GM2 with 9.3 mg of lecithin, 9.3 mg of sphingomyelin, and 18.4 mg of cholesterol (Sigma Chemical Co., St. Louis, MO). Liposomes 1 were formed by sonication by using a probe sonicator with a microtip and an energy level of 7 for 5 sec
  • Liposome preparations 2a and 2b were prepared with 200 micrograms of GM2, phosphatidyl choline (800 micrograms), cholesterol (600 micrograms), and dicetyl-phosphate (30 micrograms). Liposomes 2a were prepared with a probe sonicator as described for liposomes 1, whereas liposomes 2b were formed by sonication in water bath sonicator for 5 min (Bransonic 12; Bransonic Cleaning Equipment Company, Shelton, CT). Adjuvants to be incorporated into the liposomes were added to the GM2 before sonication.
  • mice were immunized with a given vaccine. Mice were selected randomly from the same shipment. Vaccines were administered subcutaneously in a total vol. of 0.1 ml per mouse. Two or more vaccinations containing 50 micrograms of GM2 were given at 1 mo intervals, with the exception of vaccines containing complete Freund's adjuvant (which produced marked induration and draining ulcers), no toxicity Or morbidity was detected as a consequence of the administration of any vaccine.
  • patients with AJCC stage III melanoma i.e., metastases restricted to regional skin and lymph nodes
  • patients with AJCC stage III melanoma were considered eligible if tumors and regional lymph nodes had been resected within 4 months and if they were free of detectable melanoma.
  • the studies with the whole-cell vaccines involved patients with Clark's level IV or V primary melanoma or palpable regional lymph node metastases, who were scheduled for regional lymph node dissection. In these cases, the initial vaccine was administered at least 10 days prior to surgery. None of the patients had received prior chemotherapy or radiation therapy. Patients were examined at 6-week intervals. Chest x-rays, liver function tests and urinalysis were performed at 3-month intervals.
  • GM2 Gangliosides.
  • GM2 was prepared by treating GM1 with beta-galactosidase (G.W. Jourdian, Michigan State University, Ann Arbor, MI) according to published methods (14).
  • GD1a, GD1b and GT1 were purchased from Supelco (Bellafonte, PA).
  • GD2 was generously provided by Herbert Wiegandt (University of Marburg, Federal Republic of Germany). Ganglioside extraction, identification, and quantification were performed as described (2).
  • Antibody titer was defined as the highest serum dilution yielding an 0D greater than or equal to 0.190.
  • Complement-dependent cytotoxicity assays (22) were performed with normal human serum (diluted 1:3) as the complement source.
  • Reagents for ITLC were peroxidase-conjugated goat anti-human IgM and goat anti-human IgG (Tago, Burlingame, CA) diluted 1:500.
  • GM2 vaccines without adjuvants
  • 100 micrograms of GM2 was dissolved in 1 ml of PBS.
  • 10 7 viable units of BCG Tice strain. University of Illinois
  • 3 x 10 units in the case of patients showing strong reactions to BCG were suspended in distilled water by sonication and added to tubes containing 100 micrograms of dried GM2.
  • the suspension was lyophilized and suspended in PBS shortly before vaccine administration S. minnesota mutant R595 (kindly provided by Jerry McGhee, University of Alabama) was boiled in 1% acetic acid for 1 hour as described (27), wahsed, dried, and stored frozen.
  • Sera were obtained from mice before and at regular intervals after vaccination, and were tested by the IA and PA assays on JB-RH target cells. No sera were reactive before vaccination. The reactivity of sera obtained after two vaccinations in eight separate experiments are shown in Table I. All reactions were detected by the IA assay (detecting IgM); no IgG reactions were induced. Three broad categories of vaccines were tested: traditional vaccines such as irradiated whole cells, GM2 alone, or GM2 incorporated into complete Freund's adjuvant, GM2 attached to or mixed with bacteria, and GM2 in liposomes.
  • GM2 administered in saline, in complete Freund's adjuvant, and in intralipid mixed with MPLA and BCG CWS, either with or without Cy resuited in serologic responses in only nine of 65 mice
  • Bacterial adjuvants E. coli was found to be an ineffective adjuvant (resulting in only two of 10 responses). Salmonella minnesota and BCG were moderately effective adjuvants (10 of 25 and eight of 15 responses, respectively) and the R595 mutant of Salmonella minnesota was a highly effective adjuvant (27 of 30 responses, median titer 1/64 including nine mice with titers greater than 1/128) for inducing a serologic Table 1
  • the binding capacity of R595 and BCG for GM2 was determined.
  • GM2 and 0.3 mg R595 trace amounts of GM2 were detected in the supernatant; at higher doses of R595 all of the ganglioside was in the pellet and at lower doses of R595 most of the ganglioside was in the supernatant.
  • BCG differed from R595 in that approximately 5% of the bacteria were viable and that at the highest dose tolerated by the mice (10 7 ) about 60% of GM2 was not attached to the BCG cell pellet (15,600 x G, 30 min), but was found in the supernatant.
  • Sera reactive by IA also mediate complement-dependent cytotoxicity (CDCX). Initially, sera reactive in IA tests were also tested for CDCX. Titers of reactivity were similar. In one such experiment, sera from five mice immunized with GM2 alone were nonreactive in both assays, whereas those from four of the five GM2 plus
  • mice were strongly reactive in both assays; median titer by CDCX for 50% kill was 1/40 and by IA, 1/64. We have detected no significant discrepancies between titers obtained by CDCX and IA, but have relied more heavily on IA because it is more rapid and requires less serum.
  • mice were revaccinated subcutaneously with R595-GM2 2 mo after the last vaccination.
  • the median IA titer (IgM) on JB-RH cells in this group increased from 1/80 to 1/160, but no PA or anti-IgG assay reactivity (IgG) was observed.
  • Three additional groups of four mice were given "booster" Table 2
  • mice were also tested for DTH reactivity by footpad injection of 1, 5, and 25 micrograms of GM2. No reactivity was detected.
  • Table 3 summarizes the characteristics of the whole-cell vaccine constructed from three cell lines: a mouse melanoma cell line and melanoma and astrocytoma cell lines of human origin, These cell lines were selected for high surface expression of GM2, as indicated by reactivity with a mouse mAb detecting GM2 (2).
  • Five vaccines containing purified GM2 were tested, one with GM2 alone and four with BCG or R595 as adjuvants.. In two of these trials patients were pretreated with low-dose cyclophosphamide (Cy)
  • Ganglioside content of combined vaccine ( ⁇ g/2.2 x 10 8 cells)
  • GD3 22.7 Vaccination with GM2 alone or GM2/R595 was well tolerated; no side effects were detected.
  • GM2/BCG vaccines resulted in low-grade fever (less than 39°C) and marked local ulceration in 5 of 11 patients, requiring a decrease in the BCG dose (3 x 10 organisms) or use of R595 in place of BCG for the booster vaccination. No neurologic or other detectable abnormalities were associated with GM2 vaccination.
  • Figure 1 and Table 4 show the results of ELISAs for GM2 antibody in serum from normal individuals and from nonvaccinated and vaccinated melanoma patients.
  • the frequency and titer of GM2 antibody in normal individuals and nonvaccinated melanoma patients were similar: 80% were negative and only one normal individual had a titer above 1:40.
  • GM2 antibody in high titer (1:80 or greater) in 5 of 6 vaccinated patients. No GM2 antibody was induced in patients immunized with GM2 alone. Addition of BCG to the purified GM2 vaccine resulted in GM2 antibody production, particularly in patients pretreated with Cy or given a booster immunization 12-16 weeks after the last vaccine injection. The effect of Cy was also evident in the case of GM2 vaccines with R595 as the adjuvant; 2 of 6 patients pretreated with Cy produced GM2 antibody, whereas no GM2 antibody was detected in patients not treated with Cy. R595, in contrast to BCG, was not effective as an adjuvant in booster immunizations.
  • GM2 ANTIBODY TITERS OF NORMAL INDIVIDUALS, UNTREATED MELANOMA PATIENTS, AND MELANOMA PATIENTS AFTER IMMUNIZATION WITH A WHOLE CELL VACCINE OR PURIFIED GM2 VACCINES
  • Vaccines containing GM2 alone or with complete Freund's adjuvant are not more immunogen ic than those expressing GM2 on irradiated tumor cells either. The difference is in the way the antigen is presented, and this has never been thoroughly explored by using protein or glycoprotein tumor antigens.
  • Lipopolysaccarides are made up of two distinct regions, the hydrophylic polysaccharide portion consisting of C-specific chains and basal core, and the hydrophobic lipid portion lipid A.
  • Our previous studies with whole cell vaccines (20, 22) and those described here with liposomes have identified lipid A as the single most potent adjuvant tested.
  • the R (rough) mutant 595 contains lipid A but no O-specific chains, and the core polysaccharide consists only of 2-keto-3-dioxyoctonate, which is removed by acid hydrolysis, as originally described by Galanos
  • the cell surface of acid-treated R595 is therefore highly hydrophobic and ideal for binding and concentrating added glycolipids such as GM2.
  • GM2 is concentrated on the surface and oriented in such a way that cerramide is imbedded and polysaccharide (the antigen) exposed and in close proximity to bacterial lipid A.
  • Liposomes are another method of concentrating glycolipids on a membrane with an orientation that enhances immunogenicity and of bringing them into close proximity to selected adjuvants. Our results show the importance of both liposome composition and size. They also show that one adjuvant, MPLA, was most effective in liposome preparations. As opposed to our studies with GM2-coated R595 and BCG in which the variables were limited and quickly addressed, our studies with liposomes have only served to suggest additional areas for study.
  • mice immunized in these studies continued to produce antibody for more than 6 mo without evidence of neurologic or other toxicity. This is reassuring, because GM2 is present on a small subpopulation of human and (presumably) B-6 astrocytes (1).
  • EAE experimental autoimmune encephalomyelitis
  • Nagai et al. (46) have reported that immunization of rabbits with GDIa or GM1 in complete Freund's adjuvant resulted in a syndrome similar to that described for EAE: hind leg paralysis and sometimes death.
  • melanoma cell-surface antigens that are immunogenic in the host of origin has been the object of our analysis of sera (21), cytotoxic T cells (28,29), and mAbs (15, 30) derived from melanoma patients.
  • Three general categories of melanoma cellsurface antigens that are immunogenic or potentially immunogenic in the autologous host have been defined; these range from highly restricted antigens that are detected only on autologous melanoma cells [class 1 (unique) antigens], to antigens present on a subset of melanomas as well as a limited range of other cell types (class 2 antigens), to antigens that are widely distributed on melanomas and other cell types (class 3 antigens) (21).

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Abstract

Vaccin stimulant ou améliorant, dans le sujet auquel le vaccin est administré, la production d'anticorps contre GM2. Le vaccin comprend une certaine quantité de GM2 purifié efficace pour stimuler ou améliorer la production d'anticorps dans le sujet, une quantité efficace d'un adjuvant microbien et un support pharmaceutiquement acceptable. Est également décrit un procédé de stimulation ou d'amélioration de la production d'anticorps contre le GM2 dans un sujet. Ce procédé consiste à administrer au sujet une dose efficace du vaccin ci-décrit. L'adjuvant microbien peut être le bacille Calmette-Guérin ou Salmonella minnesota R595. Est en outre décrit un procédé de traitement du cancer dans un sujet. Ce procédé consiste à administrer au sujet une dose efficace du vaccin ci-décrit. L'invention décrit également un procédé permettant de prévenir le cancer chez un sujet qui en a déjà été atteint. Le procédé consiste à administrer au sujet une dose efficace du vaccin décrit.
PCT/US1987/001049 1986-05-07 1987-05-07 Vaccin stimulant ou ameliorant la production d'anticorps contre le gm2 WO1987006840A1 (fr)

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Application Number Priority Date Filing Date Title
US044,801 1979-06-01
US86066386A 1986-05-07 1986-05-07
US860,663 1986-05-07
US4480187A 1987-04-30 1987-04-30

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JP (1) JPH01500119A (fr)
AU (1) AU603585B2 (fr)
WO (1) WO1987006840A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0473721A4 (fr) * 1989-05-25 1994-03-23 Sloan Kettering Institute For Cancer Research
WO1996040173A1 (fr) * 1995-06-07 1996-12-19 Thomas Jefferson University Extrait cellulaire tumoral a modification haptene et procede de traitement ou de depistage du cancer
WO1997034635A1 (fr) * 1996-03-21 1997-09-25 Sloan-Kettering Institute For Cancer Research Vaccin a base d'un anticorps antiidiotype
US5788985A (en) * 1993-12-29 1998-08-04 Centro De Inmunologia Molecular Vaccine composition for eliciting an immune response against N-glycolylated gangliosides and its use for cancer treatment
WO2000018432A1 (fr) * 1998-10-01 2000-04-06 Progenics Pharmaceuticals, Inc. Vaccins aux hydrates de carbone contre les maladies virales
FR2790960A1 (fr) * 1999-03-15 2000-09-22 Pf Medicament Utilisation de fractions membranaires bacteriennes a activite immunostimulante dans le traitement de cancers, leurs procedes de preparation et les compositions pharmaceutiques les contenant
US6149921A (en) * 1993-12-29 2000-11-21 Centro De Inmunologia Molecular Vaccine compositions for eliciting an immune response against N-acetylated gangliosides and their use for cancer treatment
US6432402B1 (en) 1989-05-25 2002-08-13 Sloan-Kettering Institute For Cancer Research Anti-idiotypic antibody which induces an immune response against a glycosphingolipid and use thereof
US6805862B1 (en) 1989-05-25 2004-10-19 Sloan-Kattering Institute For Cancer Research Anti-idiotypic antibody which induces an immune response against a glycosphingolipid and use thereof
US7585512B1 (en) 1990-05-08 2009-09-08 Thomas Jefferson University Composition and method of using tumor cells

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US3567585A (en) * 1963-07-12 1971-03-02 Ciba Geigy Corp Process for obtaining bcg-cultures
US4557931A (en) * 1982-12-02 1985-12-10 Regents Of The University Of California Antigenic compositions and methods for using same

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0473721A4 (fr) * 1989-05-25 1994-03-23 Sloan Kettering Institute For Cancer Research
EP0884329A1 (fr) * 1989-05-25 1998-12-16 Sloan-Kettering Institute For Cancer Research Anticorps anti-idiotypiques induisant une réaction immunitaire contre un glycosphingolipide, et son utilisation
US6432402B1 (en) 1989-05-25 2002-08-13 Sloan-Kettering Institute For Cancer Research Anti-idiotypic antibody which induces an immune response against a glycosphingolipid and use thereof
EP1334984A1 (fr) * 1989-05-25 2003-08-13 Sloan-Kettering Institute For Cancer Research Anticorps anti-idiotypiques induisant une réaction immunitaire contre un glycosphingolipide, et son utilisation
US6805862B1 (en) 1989-05-25 2004-10-19 Sloan-Kattering Institute For Cancer Research Anti-idiotypic antibody which induces an immune response against a glycosphingolipid and use thereof
US7585512B1 (en) 1990-05-08 2009-09-08 Thomas Jefferson University Composition and method of using tumor cells
US5788985A (en) * 1993-12-29 1998-08-04 Centro De Inmunologia Molecular Vaccine composition for eliciting an immune response against N-glycolylated gangliosides and its use for cancer treatment
US6149921A (en) * 1993-12-29 2000-11-21 Centro De Inmunologia Molecular Vaccine compositions for eliciting an immune response against N-acetylated gangliosides and their use for cancer treatment
WO1996040173A1 (fr) * 1995-06-07 1996-12-19 Thomas Jefferson University Extrait cellulaire tumoral a modification haptene et procede de traitement ou de depistage du cancer
WO1997034635A1 (fr) * 1996-03-21 1997-09-25 Sloan-Kettering Institute For Cancer Research Vaccin a base d'un anticorps antiidiotype
WO2000018432A1 (fr) * 1998-10-01 2000-04-06 Progenics Pharmaceuticals, Inc. Vaccins aux hydrates de carbone contre les maladies virales
FR2790960A1 (fr) * 1999-03-15 2000-09-22 Pf Medicament Utilisation de fractions membranaires bacteriennes a activite immunostimulante dans le traitement de cancers, leurs procedes de preparation et les compositions pharmaceutiques les contenant

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EP0268640A4 (fr) 1989-11-30
AU7435887A (en) 1987-12-01
EP0268640A1 (fr) 1988-06-01
AU603585B2 (en) 1990-11-22
JPH01500119A (ja) 1989-01-19

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