[go: up one dir, main page]

WO1997034921A1 - Vaccins conjugues contenant un peptide de mucine - Google Patents

Vaccins conjugues contenant un peptide de mucine Download PDF

Info

Publication number
WO1997034921A1
WO1997034921A1 PCT/US1997/004493 US9704493W WO9734921A1 WO 1997034921 A1 WO1997034921 A1 WO 1997034921A1 US 9704493 W US9704493 W US 9704493W WO 9734921 A1 WO9734921 A1 WO 9734921A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
vaccine
mucl
mucin
subject
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.)
Ceased
Application number
PCT/US1997/004493
Other languages
English (en)
Inventor
Philip O. Livingston
Shengle Zhang
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.)
Memorial Sloan Kettering Cancer Center
Original Assignee
Memorial Sloan Kettering Cancer Center
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 Memorial Sloan Kettering Cancer Center filed Critical Memorial Sloan Kettering Cancer Center
Priority to EP97916865A priority Critical patent/EP0923605A4/fr
Priority to AU25369/97A priority patent/AU734253B2/en
Priority to JP53370097A priority patent/JP2001510440A/ja
Publication of WO1997034921A1 publication Critical patent/WO1997034921A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • C07K14/4727—Mucins, e.g. human intestinal mucin
    • 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
    • A61K39/00117—Mucins, e.g. MUC-1
    • 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
    • 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
    • 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
    • A61K2039/6081—Albumin; Keyhole limpet haemocyanin [KLH]

Definitions

  • Mucins such as the mucin MUC1 are extensively glycosylated high molecular weight (> 200 kD) proteins abundantly expressed in many human cancers of epithelial origin (1-5) .
  • MUC1 contains a variable number of tandem repeats of a 20 amino ' acid peptide (PDTRPAPGSTAPPAHGVTSA) (SEQ ID. 7) in the extracellular portion of the molecule and that the most antigenic epitome recognized by anti-mucin mAbs and cytotoxic T cells is the APDTR segment within the repeats (6-8) .
  • Expression of MUC1 on normal tissues is largely restricted to the apical surface of secretory cells (1, 4) , a site with minimal access to the immune system.
  • MUC1 peptide backbones of mucins are not fully glycosylated in carcinomas, resulting in exposure to the immune system of peptide sequences which are not normally exposed (6) . Consequently, MUC1 peptide specific monoclonal antibodies show specificity for ca rcinoma-associated mucins from cancers of breast, pancreatic and ovary origin though the amino acid sequences in both normal and carcinoma mucins are probably the same (9) .
  • MUCl Human mucin MUCl is abundantly expressed in some cancers of epithelial origin and is largely restricted to the apical surface of secretory cells in normal tissues. It is therefore a potential target for cancer i munotherapy.
  • vaccines containing synthetic MUCl peptides of different lengths and sequences mixed with various adjuvants or covalently attached, using different linker methods, to protein carrier keyhole limpet hemocyanin (KLH) were studied in mice.
  • KLH protein carrier keyhole limpet hemocyanin
  • MUCl-KLH MUCl-KLH
  • QS-21 induced high titer antibody against the immunizing peptides and against MUCl-expressing tumor cells.
  • T cell responses including delayed type hypersensitivity, lymphocyte proliferation and cytotoxic T lymphocyte were not observed in mice immunized with any of these vaccines, significant protection from MUCl-expressing tumor cell challenge in mice immunized with MUCl-KLH was observed.
  • a vaccine containing MUCl-KLH conjugate prepared with m-Maleimidobenzoyl-N-hydroxysuccinimide ester linker, plus QS-21 has been constructed for testing in clinical trials.
  • This invention provides a vaccine capable of producing an immune response which recognizes a mucine, comprising an amount of mucin peptide conjugated to an immunogenic protein effective to stimulate or enhance immune response in the subject, an effective amount of an adjuvant and a pharmaceutically acceptable vehicle.
  • the subject is a human.
  • the immunogenic protein is Keyhole Limpet Hemocyanin or a derivative of Keyhole Limpet Hemocyanin.
  • the mucin is MUCl.
  • the mucin may include other mucins such as MUC 2-5. A person of ordinally skill in art would be able to apply this invention in other mucins.
  • the MUCl peptide ranges from ten amino acids to three hundred amino acids in length.
  • the effective amount of conjugated MUCl peptide is an amount between about 1 ⁇ g and about lmg.
  • the adjuvant is QS-21.
  • the effective amount of QS-21 is an amount between about lO ⁇ g and about 200 ⁇ g. In an separate embodiment, the effective amount of QS-21 is about 100 ⁇ g.
  • the subject is afflicted with cancer and the immune response produced in the subject upon administration of the vaccine effectively treats the cancer.
  • the subject is susceptible to cancer and the immune response produced in the subject upon administration of the vaccine effectively prevents the cancer.
  • cells of the cancer have the mucin on their surface.
  • the cancer is a breast cancer, prostate cancer, colon cancer, lung cancer or pancreas cancer.
  • This invention is applicable to other cancers of epithelial origin.
  • This invention also provides a method of producing an immune response which recognizes the mucin comprising administering to the subject an effective dose of the above-described vaccine.
  • This invention provi ⁇ es a method for treating cancer in a subject afflicted with cancer comprising administering to the subject an effective dose of the above-described vaccine.
  • This invention provides a method for preventing cancer in a subject susceptible to cancer comprising administering to the subject an effective dose of the above-described vaccine .
  • the immunogenic protein may be Keyhole Limpet Hemocyanin or a derivative of Keyhole Limpet Hemocyanin.
  • the adjuvant is QS-21.
  • This invention provides a vaccine capable of producing an immune response which recognizes a mucin, comprising an amount of mucin peptide conjugated to an immunogenic protein effective to stimulate or enhance immune response in the subject, an effective amount of an adjuvant and a pharmaceutically acceptable vehicle.
  • the subject is a human.
  • the effective amount of the conjugated mucin peptide may easily be determined by simple titration experiment. Animals may be immunized with different amounts of the conjugated peptide and tested with the immune response generated. The effective amount will generate an appropriate immune response.
  • the immunogenic protein is Keyhole Limpet Hemocyanin or a derivative of Keyhole Limpet Hemocyanin.
  • Other appropriate immunogenic proteins may also be used in this invention.
  • An ordinary skilled artisan may test the appropriateness of an immunogenic protein by conjugating the tested immunogenic protein with a mucin peptide known to be capable of illiciting an immune response.
  • the mucin peptide conjugated may be administrated in animals to test whether it can generate good immune responses. Proteins with good immune response are the appropriate immunogenic proteins.
  • the mucin is MUCl.
  • the mucin may include other mucins such as MUC 2-5. A person of ordinally skill in the art would be able to apply this invention in other mucins.
  • MUCl peptide ranges from thirty amino acids to three hundred amino acids in length.
  • the mucin peptide is selected from a group consisting of APDTRPAPGSTAPPAHGVTS , TAPPAHGVTSAPDTRPAPGS, APDTRPAPGSTAPPAHGVTSAPDTRPAPGS, VTSAPDTRPAPGS TAP PAHGVTSAPDTRPA , a nd (VTSAPDTRPAPGSTAPPAHG) 2 VTSAPDTRPA.
  • the mucin peptide is VTSAPDTRPAPGSTAPPAHGVTSAPDTRPA.
  • the effective amount of conjugated MUCl peptide is an amount between about 1 ⁇ g and about lmg.
  • the adjuvant is QS-21.
  • other appropriate adjuvants may be similarly used.
  • the effective amount of QS-21 is an amount between about lO ⁇ g and about 200 ⁇ g. In a further preferred separate embodiment, the effective amount of QS- 21 is about 100 ⁇ g.
  • the subject is afflicted with cancer and the immune response produced in the subject upon administration of the vaccine effectively treats the cancer.
  • the subject is susceptible to cancer and the immune response produced in the subject upon administration of the vaccine effectively prevents the cancer.
  • cells of the cancer have the mucin on their surface.
  • the cancer is a breast cancer, prostate cancer, colon cancer, lung cancer or pancreas cancer.
  • This invention is applicable to other cancers of epithelial origin.
  • This invention also provides a method for stimulating or enhancing in a subject production of an immune response which recognizes the mucin comprising administering to the subject an effective dose of the above-described vaccine.
  • This invention provides a method for treating cancer in a subject afflicted with cancer comprising administering to the subject an effective dose of the above-described vaccine.
  • This invention provides a method for preventing cancer in a subject susceptible to cancer comprising administering to the subject an effective dose of the above-described vaccine .
  • the immunogenic protein includes, but is not limited to Keyhole Limpet Hemocyanin or a derivative of Keyhole Limpet Hemocyanin.
  • the adjuvant is QS- 21.
  • the mucin is MUCl.
  • the mucin may include other mucins such as MUC 2-5. A person of ordinary- skill in the art would be able to apply this invention in other mucins.
  • the mucin may include other mucins such as MUC 2-5.
  • a person of ordinally skill in art would be able to apply this invention in other mucins.
  • MUCl peptide ranges from thirty amino acids to three hundred amino acids in length.
  • the mucin peptide is selected from a group consisting of APDTRPAPGSTAPPAHGVTS, TAPPAHGVTSAPDTRPAPGS, APDTRPAPGSTAPPAHGVTSAPDTRPAPGS,
  • VTSAPDTRPAPGSTAPPAHG 2 VTSAPDTRPA.
  • the mucin peptide is VTSAPDTRPAPGSTAPPAHGVTSAPDTRPA.
  • the effective amount of conjugated MUCl peptide is an amount between about 1 ⁇ g and about lmg.
  • the adjuvant is QS-21.
  • other appropriate adjuvants may be similarly used.
  • the effective amount of QS-21 is an amount betv/een about lO ⁇ g and about 200 ⁇ g. In a further preferred separate embodiment, the effective amount of QS- 21 is about 100 ⁇ g.
  • cells of the cancer have the mucin on their surface.
  • the cancer is a breast cancer, prostate cancer, colon cancer, lung cancer or pancreas cancer.
  • This invention is applicable to other cancers of epithelial origin.
  • HMFG-2 is a MUCl-reactive mouselgG mAb (10) .
  • 410.4 is a murine (BALB/c) mammary epithelial cancer cell line (11) and E4 is derived from a clone of 410.4 cells transfected with the MUCl gene (12) .
  • HMFG-2, 410.4 and E4 were kindly provided by Dr. Joyce Taylor- Papadimitriou (Imperial Cancer Research Fund, London, U. K.) .
  • MCF 7 is a human breast carcinoma cell line (13) .
  • mice Female BALB/c x C57BL/6 Fl mice, BALB/c x C3H Fl mice , or BALB/c mice, 6 weeks of age, were obtained from the Jackson Laboratory (Bar Harbor, Maine) .
  • Adjuvant QS-21 a purified saponin fraction (16) , was obtained from Cambridge Biotech, Inc. (Worcester, MA) .
  • Bacille Calmette-Guerin (BCG) was purchased from Connaught Laboratories (Ontario, Canada) .
  • KLH keyhole limpet hemocyanin
  • MBS conjugation method (14) One mg MBS in 70 ⁇ l dimethylformamide (Sigma Chemical Co., St. Louis, MO) was added to 5 mg KLH in 1 ml 0.01 M phosphate buffer (PB) pH 7.0. One hour later, MBS/KLH solution was applied on Sephadex G-15 column equilibrated with 0.1 M PB pH 6.0. The first peak at OD280 (MBS-KLH) was collected and mixed with 5 mg MUCl peptide and stirred at room temperature for 2 • hours. The unconjugated peptide was separated from MUCl-KLH conjugate using a Centriprep-30 concentrator (Amicon Inc., Beverly, MA) . The MUCl/KLH conjugation ratio (500/1 - 600/1) was calculated based on the starting amount of peptide and KLH and the amount of unconjugated peptide in the filtrate by spectrophotometer.
  • SPDP conjugation method (15) . Conjugation by the SPDP method was similar to that by the MBS method except that MBS was replaced by SPDP.
  • the conjugate ratio of MUCl/KLH resulting from the SPDP method was calculated in 2 different assays: 1) based on the amount of unconjugated peptide, and 2) based on the SPDP by-product (pyridine-2- thione) produced by the conjugation reaction.
  • the MUCl/KLH ratio was 400/1 -500/1 by both assays.
  • Glutaraldehyde conjugation method (14) .
  • Five mg KLH in 1 ml borate buffer pH 10 was mixed with 5 mg MUCl peptide.
  • One ml of 0.3% glutaraldehyde was added and stirred at room temperature for 2 hours . Unreacted glutaraldehyde was blocked by adding 0.25 ml 1 M glycine for 30 min.
  • the MUCl- KLH solution was dialysed against PBS overnight. Because glutaraldehyde interferred with the absorbance of unconjugated peptide at OD215, the ratio of MUCl/KLH was assumed based on the starting ratio, 500/1.
  • mice were immunized with 8-15 ⁇ g MUCl peptide alone or conjugated to KLH plus 8-10 ⁇ g QS-21 or 5 x 10 5 BCG, 2-3 times at one week intervals. Eight to ten days after the 2nd or 3rd immunization, mice were bled and the sera separated for testing with ELISA and flow cytometry assays.
  • ELISA Serological assays. ELISA. ELISAs were performed as previously described (17) . MUCl peptide in 0.1 M carbonate buffer pH 9.6 were coated on ELISA plates at 0.1 ⁇ g/well. A series of antiserum dilutions were incubated with the • coated peptide for 1 hour. Secondary antibodies were alkaline phosphatase-con ugated goat anti-mouse IgG or IgM at a dilution of 1/200 (Southern Biotechnology Associates, Inc., Birmingham, AL) . ELISA titer is defined as the highest dilution yielding an absorbance of 0.1 or greater over that of normal mouse sera. MAb HMFG-2 was used as positive control in each assay.
  • Tumor cells (2 x 10 5 ) were incubated with 40 1 of 1/30 diluted antisera or 1/2 diluted mAb supernatant for 30 min on ice. After washing with 3% fetal calf serum/phosphate buffered saline, the cells were incubated with 20 / l of 1/15 diluted fluorescein-isothiocyanate- labeled goat anti-mouse IgM or IgG (Southern Biotechnology Associates, Inc., Birmingham, AL) . The positive population of the stained cells were quantitated by flow cytometry
  • T lymphocyte assays Proliferative assay (19) . Lymphocytes
  • mice (2 x loVwell) were prepared from the spleens of mice seven days after the 2nd immunization, and incubated with MUCl peptide (0.1-10 ⁇ g/ml) or KLH (1-20 ⁇ g/ml) in 37°C/5% C02 for 3-5 days. Eighteen hours after adding 0.5 ⁇ Ci 3 H- Thymidine (ICN, Irvine, CA) per well, the cells were processed and analyzed with a 1204 Betaplate (Wallac Oy, Finland) .
  • MUCl peptide 0.1-10 ⁇ g/ml
  • KLH 1-20 ⁇ g/ml
  • Delayed type hypersensitivity (20) (20) Two weeks after the 2nd immunization, 5 ⁇ g MUCl peptide or KLH were injected in 20 ⁇ l PBS into the hind foodpad. Footpad thickness was measured at 24 and 48 hours.
  • Cytotoxic T lymphocyte (CTD assay (21) . Seven days after the 2nd immunization, splenic lymphocytes were sensitized in vitro with 1-8 ⁇ g/ml MUCl peptide and 10 unit/ml IL-2 (Boehringer Mannheim, Germany) for 7-10 days. The sensitized lymphocytes were then incubated with europium- labeled E4 or 410.4 cells at ratios of 10:1-100:1 for 4 hours. Percent release of europium from target cells were measured with a time-resolved 1232 Delfia fluorometer (Wallac Oy, Finland) (18) .
  • mice were injected i.v. with 2 x 10 5 E4 cells. Twenty five days later, the mice were sacrificed, the lungs fixed with 10% formaldehyde, and the number of tumor colonies in the lungs were counted, as previously described (22) .
  • mice immunized with MUCl (30) -KLH but not those immunized with unconjugated MUCl, also showed strong reactivity with MUCl- expressing E4 murine breast cancer cells and MCF 7 human breast cancer cells.
  • MUCl (20) -KLH (glutaraldehyde) MUCl (20) - KLH (SPDP) and MUCl (30A) -KLH (SPDP) were 59%, 32% and 61% respectively.
  • MUC1(20A) conjugates on the other hand, no obvious difference in titer or % positive cell were observed between the MBS and SPDP methods. Reactivity against the MUCl-negative cell line 410.4 was minimal in all groups.
  • mice immunized with MUCl (20) -KLH (SPDP) (1:50) were obviously lower than that from mice immunized with MUCl (20A) -KLH (SPDP) (1:4050) .
  • the median % positive cells by flow cytometry with sera from these two groups was the same (32%) .
  • mice immunized with MUCl (20) -KLH (MBS) were significantly higher than that for mice immunized with MUCl (20A) -KLH (MBS) , 1:4050 and 54% respectively (p ⁇ 0.05) .
  • MUC1(30)-KLH was compared with MUCl (30A) -KLH (Table 2) , no obvious difference in serological response was found.
  • mice in Tables 3 and 4 were tested for DTH. Forty eight hours after footpad injection with 5 ⁇ g MUCl peptide, the average footpad thickness for mice immunized with MUCl peptides and MUCl-KLH constructs were 1.72 +/- 0.05 mm
  • mice immunized with MUCl (30) -KLH produced IgG antibody at a mean titer of 1:5940 with good E4 cell surface reactivity (mean % positive cells, 52%) .
  • the mean number of lung colonies from 10 mice was 19 and 20 for PBS and KLH control groups respectively, while only 1 for the MUCl (30A) -KLH group (p ⁇ 0.01) .
  • a BALB/c x C3H Fl were immunized twice at one week interval with 8 g MUCl (30A) -KLH plus 8 g QS-21 /mouse and boosted one week after the 2nd vaccine with 8 g MUC1(30A) peptide plus 8 g QS-21.
  • KLH group were given the same amount of KLH as the MUCl (30A) -KLH group.
  • 2 x 10 s E4 cells were injected i.v. to all the groups. Twenty eight days after E4 cell injection, mice were sacrificed to check the matastastic colonies in lungs . Mice were bled 10 days after 2nd vaccine for ELISA and flow cytometry assay.
  • MUCl specific antibodies have been detected in sera from occasional breast, pancreatic and colon cancer patients (2, 23) . This suggests that MUCl can be recognized by the human immune system, and raised the possibility that immunity against tumor cells expressing MUCl might be induced by properly constructed MUCl vaccines.
  • Vaccines containing unconjugated MUCl peptides plus QS-21 or BCG failed to induce antibody.
  • MUCl peptides were conjugated to KLH, plus QS-21, high titer IgM and, especially, IgG antibodies against MUCl antigen were successfully induced.
  • the reactivity of these antisera with MUCl-expressing mouse tumor E4 and human breast tumor MCF7 cells was strong, similar to mAb HMFG-2.
  • MBS was found to be the best linker for preparing MUCl-KLH conjugates, inducing the most favorable antibody in both titer and specificity.
  • T lymphocyte immunity against MUCl peptide in unimmunized cancer patients has been documented (24, 25) .
  • QS-21 is an immunological adjuvant known to be capable of inducing CTL against other soluble protein antigens (29) .
  • Others have attempted to induce T cell responses with synthetic MUCl peptide, MUCl conjugates, vaccinia expressing MUCl or MUCl expressed on whole tumor cells (5, 26-28) .
  • MUCl peptides (containing 20 or 30 amino acids) plus adjuvants
  • MUCl-KLH MUCl-KLH
  • linker MBS m-Maleimidobenzoyl-N-hydroxysuccinimide ester
  • QS-21 induced high titer antibody against the immunizing peptides, median titer 1:800 for IgM and 1:307,200 for IgG.
  • these antisera showed strong reactivity with MUCl-expressing mouse tumor E4 cells and human breast MCF-7 cells, similar to the MUCl- reactive mAb HMFG-2. Based on these studies, a vaccine containing MUCl-KLH conjugate prepared with linker MBS, plus QS-21, has been constructed for testing in clinical trials.
  • the mucin MUC-1 is expressed on breast carcinomas in an under glycosylated configuration and is therefore a target for immune recognition.
  • a 30 amino acid (aa) sequence of MUC-1 has been synthesized and in order to agument its immunogenicity, has been covalently linked to KLH and mixed with the immune adjuvant QS21.
  • Eligiblity criteria include: patients with stage 4 NED (no evidence of disease) , elevated CEA or CA15-3 levels and NED, or initially unresectable stage 3 post adjuvant therapy (tx) .
  • Five vaccines, each containing 100 meg of MUC-1 peptide, were given on weeks 1, 2, 3, 7, 19. Thus far five pts are on study, although only 5 patients have received >_ 3 vaccinations.
  • Stage IV no evidence of disease NED
  • breast cancer patients BCPts
  • earlier stage BCPts except for rising CEA or BR2729 levels are at high risk for overt recurrence and might benefit from immunotherapy.
  • Mucin MUC-1 found on most breast carcinomas, is a potential target.
  • a synthetic 30 amino acid (aa) sequence of MUC-1 has been conjugated with KLH and mixed with the immune adjuvant QS- 21 to increase immune recognition.
  • Nine patients (ages 43- 61) have been vaccinated: eight stage IV NED, one stage II with increased CEA level and NED, all but one stage IV NED patient on hormonal treatment. All patients received five doses of 100 meg MUC-1 s.c. given on weeks 1, 2, 3, 7, and 19.
  • IgG titers Five patients maintain IgG titers (range 320-1280) between six-twelve months following the last vaccine. Analysis of IgG subclass in eight patients reveal predominantly IgGl and IgG3. Immune adherence rosetting against MCF-7 cell lines revealed an increase in IgM titers in 6/7 patients. Inhibition assays demonstrate that all sera react exclusively with the APDTRPA determinant of MUC-l. No evidence for augmentation of T cell immunity was found. This MUC-1 vaccine is immunogenic in breast cancer patients who are NED.
  • the mucin MUC-1 is expressed on breast cancers in an underglycosylated form compared to normal tissues and is therefore a potential target for cancer immunotherapy.
  • MUC-1 contains multiple tandem repeats of the 20 amino acid peptide (VTSAPDTRPAPGSTAPPAHG) .
  • the APDTR epitope is particularly immunogenic since it is recognized by a variety of murine monoclonal antibodies and immune sera, and by some sera and cytotoxic T cells from unimmunized patients with epithelial cancers.
  • a 30 amino acid peptide VTSAPDTRPAPGSTAPPAHGVTSAPDTRPA was prepared with cysteine at the N-terminal end for chemical conjugated to keyhole limpet hemocyanin (KLH) .
  • MOLECULE TYPE DNA (genomic)
  • MOLECULE TYPE DNA (genomic)
  • MOLECULE TYPE DNA (genomic)
  • MOLECULE TYPE DNA (genomic)

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Molecular Biology (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Oncology (AREA)
  • Microbiology (AREA)
  • Epidemiology (AREA)
  • Mycology (AREA)
  • Immunology (AREA)
  • Zoology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Toxicology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Vaccin susceptible de produire une réaction immunitaire qui reconnaît une mucine, comprenant une certaine quantité de peptide de mucine conjugué avec une protéine immunogène qui stimule ou accroît la réaction immunitaire du sujet, une quantité efficace d'un adjuvant et un excipient acceptable sur le plan pharmaceutique. L'invention porte aussi sur une technique de stimulation ou d'augmentation de la production d'une réaction immunitaire qui reconnaît une mucine, comprenant l'administration au sujet du vaccin décrit ci-dessus.
PCT/US1997/004493 1996-03-20 1997-03-20 Vaccins conjugues contenant un peptide de mucine Ceased WO1997034921A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP97916865A EP0923605A4 (fr) 1996-03-20 1997-03-20 Vaccins conjugues contenant un peptide de mucine
AU25369/97A AU734253B2 (en) 1996-03-20 1997-03-20 Conjugated mucin peptide vaccines
JP53370097A JP2001510440A (ja) 1996-03-20 1997-03-20 ムチン接合体ペプチドワクチン

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US1377596P 1996-03-20 1996-03-20
US60/013,775 1996-03-20

Publications (1)

Publication Number Publication Date
WO1997034921A1 true WO1997034921A1 (fr) 1997-09-25

Family

ID=21761689

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/004493 Ceased WO1997034921A1 (fr) 1996-03-20 1997-03-20 Vaccins conjugues contenant un peptide de mucine

Country Status (5)

Country Link
EP (1) EP0923605A4 (fr)
JP (1) JP2001510440A (fr)
AU (1) AU734253B2 (fr)
CA (1) CA2249395A1 (fr)
WO (1) WO1997034921A1 (fr)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999033869A3 (fr) * 1997-12-24 1999-12-23 Corixa Corp Composes destines a l'immunotherapie et au diagnostic du cancer du sein, et leur mode d'utilisation
WO2000052046A1 (fr) * 1999-03-01 2000-09-08 Imperial Cancer Research Technology Limited Glycopeptide immunomodulatrice
WO2001046228A3 (fr) * 1999-12-22 2002-01-17 Glaxo Group Ltd Améliorations apportées à une vaccination par acide nucléique
US6379951B1 (en) 1997-12-24 2002-04-30 Corixa Corporation Compounds for immunotherapy of breast cancer and methods for their use
US6410507B1 (en) 1997-12-24 2002-06-25 Corixa Corporation Compounds for immunotherapy and diagnosis of breast cancer and methods for their use
US6432707B1 (en) 1997-12-24 2002-08-13 Corixa Corporation Compositions and methods for the therapy and diagnosis of breast cancer
US6468758B1 (en) 1998-09-23 2002-10-22 Corixa Corporation Compositions and methods for ovarian cancer therapy and diagnosis
AU2003232994B2 (en) * 2002-04-22 2009-07-23 Recopharma Ab Lewis Y epitope modified polypeptide, or mucin fusion polypeptide, tumor vaccines
US8198400B2 (en) 2001-03-27 2012-06-12 Oncothyreon, Inc. Vaccine for modulating between T1 and T2 immune responses
US8329639B2 (en) 2011-02-24 2012-12-11 Oncothyreon Inc. MUC1 based glycolipopeptide vaccine with adjuvant
US8871250B2 (en) 2005-06-28 2014-10-28 Oncothyreon Inc. Method of treating patients with a mucinous glycoprotein (MUC-1) vaccine
US9173929B2 (en) 2004-04-01 2015-11-03 Oncothyreon Inc. Mucinous glycoprotein (MUC-1) vaccine
US10251944B2 (en) 2016-01-19 2019-04-09 Pfizer Inc. Cancer vaccines

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5229289A (en) * 1988-03-11 1993-07-20 The Biomembrane Institute Monoclonal antibodies and vaccine development directed to human cancer-associated antigens by immunization with animal and human and with synthetic carbohydrate-carrier conjugates
US5455034A (en) * 1992-06-26 1995-10-03 Kansas State University Research Foundation Fusobacterium necrophorum leukotoxoid vaccine

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5744144A (en) * 1993-07-30 1998-04-28 University Of Pittsburgh University Patent Committee Policy And Procedures Synthetic multiple tandem repeat mucin and mucin-like peptides, and uses thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5229289A (en) * 1988-03-11 1993-07-20 The Biomembrane Institute Monoclonal antibodies and vaccine development directed to human cancer-associated antigens by immunization with animal and human and with synthetic carbohydrate-carrier conjugates
US5455034A (en) * 1992-06-26 1995-10-03 Kansas State University Research Foundation Fusobacterium necrophorum leukotoxoid vaccine

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CANCER IMMUNOLO. IMMUNOTHER., 1993, Vol. 36, DING et al., "Immunogenicity of Synthetic Peptides Related to the Core Peptide Sequence Encoded by the Human MUC1 Mucin Gene: Effect of Immunization on the Growth of Murine Mammary Adenocarcinoma Cells Transfected With the Human MUC1 Gene", pages 9-17. *
CANCER RESEARCH, 01 October 1994, Vol. 54, APOSTOLOPOULUS et al., "Murine Immune Response to Cells Transfected With Human MUC1: Immunization With Cellular and Synthetic Antigens", pages 5186-5193. *
INT. J. CANCER, 1994, Vol. 57, HOLLINGSWORTH et al., "Expression of MUCI, MUC2, MUC3 and MUC4 MUCIN mRNAs in Human Pancreatic and Intestinal Tumor Cell Lines", pages 198-203. *
PROCEEDINGS OF THE AMERICAN ASSOCIATION FOR CANCER RESEARCH, March 1995, Vol. 36, FINN, "Immunity to Epithelial Tumors and Mucin-Based Vaccine Design", page 675. *
See also references of EP0923605A4 *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999033869A3 (fr) * 1997-12-24 1999-12-23 Corixa Corp Composes destines a l'immunotherapie et au diagnostic du cancer du sein, et leur mode d'utilisation
US6379951B1 (en) 1997-12-24 2002-04-30 Corixa Corporation Compounds for immunotherapy of breast cancer and methods for their use
US6410507B1 (en) 1997-12-24 2002-06-25 Corixa Corporation Compounds for immunotherapy and diagnosis of breast cancer and methods for their use
US6432707B1 (en) 1997-12-24 2002-08-13 Corixa Corporation Compositions and methods for the therapy and diagnosis of breast cancer
US6468758B1 (en) 1998-09-23 2002-10-22 Corixa Corporation Compositions and methods for ovarian cancer therapy and diagnosis
WO2000052046A1 (fr) * 1999-03-01 2000-09-08 Imperial Cancer Research Technology Limited Glycopeptide immunomodulatrice
WO2001046228A3 (fr) * 1999-12-22 2002-01-17 Glaxo Group Ltd Améliorations apportées à une vaccination par acide nucléique
US8198400B2 (en) 2001-03-27 2012-06-12 Oncothyreon, Inc. Vaccine for modulating between T1 and T2 immune responses
US8552145B2 (en) 2001-03-27 2013-10-08 Oncothyreon Inc. Vaccine for modulating between T1 and T2 immune responses
AU2003232994B2 (en) * 2002-04-22 2009-07-23 Recopharma Ab Lewis Y epitope modified polypeptide, or mucin fusion polypeptide, tumor vaccines
US9173929B2 (en) 2004-04-01 2015-11-03 Oncothyreon Inc. Mucinous glycoprotein (MUC-1) vaccine
US8871250B2 (en) 2005-06-28 2014-10-28 Oncothyreon Inc. Method of treating patients with a mucinous glycoprotein (MUC-1) vaccine
US9119784B2 (en) 2005-06-28 2015-09-01 Oncothyreon Inc. Method of treating patients with a mucinous glycoprotein (MUC-1) vaccine
US8329639B2 (en) 2011-02-24 2012-12-11 Oncothyreon Inc. MUC1 based glycolipopeptide vaccine with adjuvant
US8889616B2 (en) 2011-02-24 2014-11-18 Oncothyreon Inc. MUC1 based glycolipopeptide vaccine with adjuvant
US10251944B2 (en) 2016-01-19 2019-04-09 Pfizer Inc. Cancer vaccines
US11058753B2 (en) 2016-01-19 2021-07-13 Pfizer Inc. Cancer vaccines

Also Published As

Publication number Publication date
AU2536997A (en) 1997-10-10
JP2001510440A (ja) 2001-07-31
EP0923605A4 (fr) 2003-01-02
CA2249395A1 (fr) 1997-09-25
EP0923605A1 (fr) 1999-06-23
AU734253B2 (en) 2001-06-07

Similar Documents

Publication Publication Date Title
EP0859627B1 (fr) Agents mimetiques peptidiques dans la therapie du cancer
US6177256B1 (en) Antigen carbohydrate compounds and their use in immunotherapy
von Mensdorff-Pouilly et al. Human MUC1 mucin: a multifaceted glycoprotein
Apostolopoulos et al. Cellular mucins: targets for immunotherapy
Palmer et al. Phase I study of the BLP25 (MUC1 Peptide) liposomal vaccine for active specific immunotherapy in stage IIIB/IV non–small-cell lung cancer
US6548643B1 (en) Antigen carbohydrate compounds and their use in immunotherapy
AU734253B2 (en) Conjugated mucin peptide vaccines
Ragupathi et al. A preclinical study comparing approaches for augmenting the immunogenicity of a heptavalent KLH-conjugate vaccine against epithelial cancers
AU745555B2 (en) Fucosyl GM1-KLH conjugate vaccine against small cell lung cancer
US8916514B2 (en) CASB7439 constructs
US12311019B2 (en) Vaccine composition and uses thereof
US20180264093A1 (en) Immunogenic glycopeptide compounds, pharmaceutical compositions and uses thereof
Ragupathi et al. The case for polyvalent cancer vaccines that induce antibodies
WO2000038515A1 (fr) Mimetiques peptidiques utiles pour traiter des maladies
Apostolopoulos et al. Studies of MUC1 peptides
AU780395B2 (en) Mucin-1 derived antigens and their use in immunotherapy
Ciborowski et al. MUC1 mucin as a tumor antigen in breast cancer
LIVINGSTON 7. ANTIBODY INDUCING POLYVALENT CANCER VACCINES
Fiore et al. Synthetic Vaccines against Cancers
Taylor-Papadimitriou et al. MUC1 vaccines and breast cancer
Livingston et al. Carbohydrate vaccines against cancer

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA JP MX US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
ENP Entry into the national phase

Ref document number: 2249395

Country of ref document: CA

Ref country code: CA

Ref document number: 2249395

Kind code of ref document: A

Format of ref document f/p: F

ENP Entry into the national phase

Ref country code: JP

Ref document number: 1997 533700

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 1997916865

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1997916865

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1997916865

Country of ref document: EP