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WO1994001560A1 - Proteines et peptides allergenes tires du pollen du cedre du japon - Google Patents

Proteines et peptides allergenes tires du pollen du cedre du japon Download PDF

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Publication number
WO1994001560A1
WO1994001560A1 PCT/US1993/000139 US9300139W WO9401560A1 WO 1994001560 A1 WO1994001560 A1 WO 1994001560A1 US 9300139 W US9300139 W US 9300139W WO 9401560 A1 WO9401560 A1 WO 9401560A1
Authority
WO
WIPO (PCT)
Prior art keywords
cjl
peptide
allergen
cryj
japanese cedar
Prior art date
Application number
PCT/US1993/000139
Other languages
English (en)
Inventor
Irwin J. Griffith
Joanne Pollock
Julian F. Bond
Richard D. Garman
Mei-Chang Kuo
Original Assignee
Immulogic Pharmaceutical Corporation
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
Priority claimed from PCT/US1992/005661 external-priority patent/WO1993001213A1/fr
Application filed by Immulogic Pharmaceutical Corporation filed Critical Immulogic Pharmaceutical Corporation
Priority to EP93903013A priority Critical patent/EP0659214A1/fr
Priority to JP50326994A priority patent/JP4102432B2/ja
Priority to AU34384/93A priority patent/AU3438493A/en
Publication of WO1994001560A1 publication Critical patent/WO1994001560A1/fr
Priority to KR1019950700826A priority patent/KR950703058A/ko
Priority to US08/467,023 priority patent/US6090386A/en
Priority to US09/240,203 priority patent/US6982326B1/en
Priority to US10/931,260 priority patent/US8540999B2/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/415—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from plants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies

Definitions

  • the antibodies involved in atopic allergy belong primarily to the IgE class of immunoglobulins.
  • IgE binds to mast cells and basophils.
  • the IgE may be cross-linked on the cell surface, resulting in the physiological effects of IgE-antigen interaction.
  • physiological effects include the release of, among other substances, histamine, serotonin, heparin, a chemotactic factor for eosinophilic leukocytes and/or the leukotrienes, C4, D4, and E4, which cause prolonged constriction of bronchial smooth muscle cells (Hood, L.E. et al.
  • Japanese cedar (Sugi; Cryptomeria japonica) pollinosis is one of the most important allergic diseases in Japan. The number of patients suffering from this disease is on the increase and in some areas, more than 10% of the population are affected. Treatment of Japanese cedar pollinosis by administration of Japanese cedar pollen extract to effect hyposensitization to the allergen has been attempted. Hyposensitization using Japanese cedar pollen extract, however, has drawbacks in that it can elicit anaphylaxis if high doses are used, whereas when low doses are used to avoid anaphylaxis, treatment must be continued for several years to build up a tolerance for the extract.
  • U.S. patent 4,939,239 issued July 3, 1990 to Matsuhashi et al. discloses a hyposensitization agent comprising a saccharide covalently linked to a Japanese cedar pollen allergen for hyposensitization of persons sensitive to Japanese cedar pollen.
  • This hyposensitization agent is reported to enhance the production of IgG and IgM antibodies, but reduce production of IgE antibodies which are specific to the allergen and responsible for anaphylaxis and allergy.
  • Fig. lb shows an SDS-PAGE (12.5%) analysis of the fractions from the major peak shown in Fig la;
  • Fig. 2 shows a Western blot of isoforms of purified native Cryj I proteins separated by SDS-PAGE and probed with mAB CBF2;
  • Fig. 3 is a graphic representation of allergic sera titration of different purified fractions of purified native Cryj I using plasma from a pool of fifteen allergic patients;
  • Figs. 4a-b show the composite nucleic acid sequence from the two overlapping clones JC 71.6 and pUC19JC91a coding for Cryj I.
  • the complete cDNA sequence for Cryj I is composed of 1312 nucleotides, including 66 nucleotides of 5' untranslated sequence, an open reading frame starting with the codon for an initiating methionine of 1122 nucleotides, and a 3' untranslated region.
  • Figs. 4a-b also show the deduced amino acid sequence of Cryj I;
  • Fig. 10b is a graphic representation of the results of a capture ELISA using rabbit anti-Ami? al and II, wherein the wells were coated with 20 ⁇ g/ml CBF2 (IgG), PBS was used as a negative antigen control and the antigen was purified recombinant Cryj I;
  • Fig. 11 is a graphic representation of a histamine release assay performed on one Japanese cedar pollen allergic patient using SPE from Japanese cedar pollen, purified native Cryj I and recombinant Ct j I as the added antigens; and
  • Fig. 17 shows the nucleotide sequence of Jun v I; this sequence is a composite from the two overlapping cDNA clones pUC19JV46a and pUC19JV49iia coding for Jun v I; the complete cDNA sequence for Jun v I is composed of 1278 nucleotides, including 35 nucleotides of 5' untranslated sequence, an open reading frame of 1,110 nucleotides, and a 3' untranslated region; Fig. 17 also show the deduced amino acid sequence of Jun v I. Fig. 18 shows various peptides of desired lengths derived from Ctyj I.
  • Figs. 19a and 19b show Northern blots of pollen-derived RNA probed with Cryj cDNA for identification of mRNA capable of encoding Ct j I or a
  • NO: 1 contains a 21 amino acid leader sequence from base 66 through base 128.
  • This leader sequence is cleaved from the mature protein which is encoded by bases 129 through 1187.
  • the deduced amino acid sequence of Cryj I is also shown in Figs. 4a and 4b (SEQ ID NO: 2).
  • the nucleic acid sequence of the invention codes for a protein having a predicted molecular weight of 38.5 kDa, with a pi of 7.8, and five potential N-linked glycosylation sites. Utilization of these glycosylation sites will increase the molecular weight and affect the pi of the mature protein.
  • the deduced amino acid sequence for the mature protein encoded by the nucleic acid sequence of the invention is identical with the known NH2-terminal and internal amino acid sequences reported by Taniai et al., supra.
  • family members of Ctyj I there may be one or more family members of Ctyj I.
  • family members are defined as proteins related in function and amino acid sequence to Cryj I but encoded by genes at separate genetic loci.
  • Host cells can be transformed to express the nucleic acid sequences of the invention using conventional techniques such as calcium phosphate or calcium chloride co-precipitation, DEAE-dextran-mediated transfection, or electroporation. Suitable methods for transforming the host cells may be found in Sambrook et al. supra, and other laboratory textbooks.
  • the nucleic acid sequences of the invention may also be synthesized using standard techniques.
  • Administration of the therapeutic compositions of the present invention to an individual to be desensitized can be carried out using known procedures at dosages and for periods of time effective to reduce sensitivity (i.e., reduce the allergic response) of the individual to the allergen.
  • Effective amounts of the therapeutic compositions will vary according to factors such as the degree of sensitivity of the individual to Japanese cedar pollen, the age, sex, and weight of the individual, and the ability of the protein or fragment thereof to elicit an antigenic response in the individual.
  • the active compound i.e., protein or fragment thereof
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions of dispersion.
  • the composition must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glyceral, propylene glycol, and liquid polyetheylene glycol, and the like). suitable mixtures thereof, and vegetable oils.
  • DNA of the present invention can be used to identify, in other types of plants, preferably related families, genera, or species such as Juniperus, or Cupressus, sequences encoding polypeptides having amino acid sequences similar to that of Japanese cedar pollen allergen Cryj I, and thus to identify allergens in other species.
  • the present invention includes not only Ctyj I, but also other allergens encoded by DNA which hybridizes to DNA of the present invention.
  • Peptides are selected based on various factors, including the strength of the T cell response to the peptide (e.g., stimulation index), the frequency of the T cell response to the peptide in a population of individuals sensitive to Japanese cedar pollen, and the potential cross-reactivity of the peptide with other allergens from other species of trees as discussed earlier (e.g. Cupressus sempervirens, Cupressus arizonica, Juniperus virginiana, Juniperus sabinoides, etc.) or ragweed (Amb a I) .
  • stimulation index e.g., stimulation index
  • the frequency of the T cell response to the peptide in a population of individuals sensitive to Japanese cedar pollen e.g. Cupressus sempervirens, Cupressus arizonica, Juniperus virginiana, Juniperus sabinoides, etc.
  • ragweed Amb a I
  • Region 2 comprises amino acid residues 61-120 of Cry J I
  • Region 3 comprises amino acid residues 131-180 of Ctyj I
  • Region 4 comprises amino acid residues 191-280 of Cryj I
  • Region 5 comprises amino acid residues 291-353 of the Cr j I.
  • Amplified DNA was recovered by sequential chloroform, phenol, and chloroform extractions, followed by precipitation at -20°C with 0.5 volumes of 7.5 ammonium acetate and 1.5 volumes of isopropanol. After precipitation and washing with 70% ethanol, the DNA was simultaneously digested with Xba
  • GCAATGTACATAGGCAT-3' (SEQ ID NO: 11) and corresponds to the non- coding strand sequence of CP- 13 SEQ ID NO: 10).
  • CP- 15 has the sequence 5'- TCCAATTCTTCTGATGGT-3' ((SEQ ID NO: 12) which encodes amino acids 169-174 of Cryj I (SerAsnSerSerAspGly, amino acids 169 through 174 of SEQ ID NO: 1).
  • CP-16 has the sequence 5'- TTTTGTCAATTGAGGAGT-3' (SEQ ID NO: 13) which is the non-coding strand sequence which corresponds to coding strand sequence encoding amino acids 335-340 of Cryj I
  • the nucleotide sequence 5'-CCTGCAGAAGCTT-3' (bases 1 through 13 of SEQ. ID # 14) represents Pst I and Hin dill restriction sites added for cloning purposes.
  • the nucleotide sequence 5'-TCA-3' (bases 13 through 15 of SEQ. ID # 14) correspond to the non-coding strand sequence of a stop codon. All of the amplifications yielded products of the expected size when viewed on ethidium bromide (EtBr)-stained agarose gels. Two of these primer pairs were used in amplifications whose products were cloned into pUC19 for full-length sequencing.
  • the PCR reaction with CP-10 (SEQ.
  • EBV-transformed cell lines were ⁇ -irradiated with 25,000 Rad and used as antigen presenting cells in secondary proliferation assays and secondary bulk stimulations. These cell lines were also used as a control in the immuno-fluorescence flow cytometry analysis. These EBV-transformed cell lines were made by incubating 5 X 10 ⁇ PBL with 1 ml of B-59/8 Marmoset cell line (ATCC CRL1612, American Type Culture Collection, Rockville, MD) conditioned medium in the presence of 1 ⁇ g/ml phorbol 12-myristate 13-acetate (PMA) at 37°C for 60 minutes in 12 X 75 mm polypropylene round-bottom Falcon snap cap tubes (Becton Dickinson Labware, Lincoln Park, NJ).
  • B-59/8 Marmoset cell line ATCC CRL1612, American Type Culture Collection, Rockville, MD
  • PMA phorbol 12-myristate 13-acetate
  • FIG. 8a shows the direct binding assay to the SPE with seven individual plasma samples.
  • Fig. 8b the binding results with the denatured SPE demonstrates the marked decrease in reactivity following this treatment.
  • Ctyj I was detected with a rabbit polyclonal antisera against the Amb a I & II protein family.
  • These ragweed proteins have high sequence identity (46%) with Cryj I and this antisera can be used as a cross reactive antibody detection system.
  • these data demonstrate a marked loss in IgE reactivity following denaturation of the Japanese cedar pollen SPE.
  • the recombinant Cryj I protein (rCryj I), expressed in bacteria and then purified (as described in Example 5), has been examined for IgE reactivity.
  • the first method applied to this examination was direct ELISA where wells were coated with the recombinant Cryj I and IgE binding was assayed on individual patients.
  • Fig. 9 is the graphic representation of this direct ELISA.
  • the only positive signals on this data set are from the two control antisera rabbit polyclonal anti-Amb a I & II prepared by conventional means (Rabbit anti-Amb a I & JJ) and CBF2, a monoclonal antibody raised against Amb a I that cross reacts with Cryj I .
  • Rabbit anti-Amb a I & JJ monoclonal antibody raised against Amb a I that cross reacts with Cryj I .
  • 10a and 10b are the graphed results of these assays.
  • the pooled human plasma (PHP) 15 patients was used.
  • PHP human plasma
  • the conclusion from these results is that there is no indication of any specific binding of human allergic IgE to rCryj I by this method of analysis.
  • the capture of rCrv J I works as evidenced by the control antibody binding curve, shown in Fig. 10b.
  • the lack of IgE binding to E. coli expressed rCrv J I may be due to absence of carbohydrate or any other post-translational modification and/or that the majority of IgE cannot react with denatured Cryj I.
  • RAST, competition ELISA and Western blotting data also demonstrates no specific IgE reactivity to the rCry J I (data not shown).
  • oligonucleotide primer pairs used were: CP-9/CP- 17, CP10/CP- 17, CP-10/CP-16, CP-10/CP-19, CP-10/CP-18, CP-13/CP-17, and CP-13/CP-19.
  • CP- 10 was used in the majority of the reactions as the 5' primer since it has been reported by Gross et. al. (1978) Scand. J. Immunol. 8: 437-441 that the first 5 amino-terminal amino acids of J. sabinoides are identical to those of Cr j I.
  • nucleotide 33 can also be an A or C.
  • oligonucleotide APA was used in a primary PCR reaction with Jl for J. sabinoides and J. virginiana, followed by secondary amplifications with J2 (for J. sabinoides) or J3 (for J virginiana) and APA. No specific product was identified from these amplifications.
  • the degenerate primer CP-57 was then synthesized.
  • AAAACTATTCCCTTCACT-3' wherein A at position 1 can also be G, and A at position 4 can also be T.
  • This is the non-coding strand sequence that corresponds to coding strand sequence (nucleotides 875-892 of Fig. 16) encoding amino acids SerGluGlyAsnSerPhe of Jun s I (amino acids 263-268 of Fig. 16).
  • J6 has the sequence 5'-TAGGACATAGTGATTCAT-3' (nucleotides 700-717 of
  • nucleotides 10-27 are the non-coding strand sequence complementary to nucleotides 1140- 1157 from the 3' untranslated region of Jun s I (Fig. 16).
  • the PCR product, designated JS53ii gave a band of approximately 1200 bp when examined on a 1% agarose minigel stained with ⁇ tBr.
  • the DNA from the JS53ii PCR was recovered as described in Example 3. After precipitation and washing with 70% EtOH, the DNA was simultaneously digested with EcoR I and BamH I in a 15 ⁇ l reaction and electrophoresed through a preparative 1% GTG SeaPlaque low melt gel (FMC, Rockport, M ⁇ ).
  • ORGANISM Crytpomeria japonica

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
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  • Peptides Or Proteins (AREA)

Abstract

Peptides isolés de l'allergène protéique du pollen du cèdre du Japon Cry j I. Les peptides concernés par la présente invention comportent au moins un épitope des lymphocytes T, ou de préférence au moins deux épitopes de lymphocytes T de Cry j I. La présente invention concerne également des peptides modifiés ayant des propriétés thérapeutiques similaires ou améliorées par rapport à l'allergène correspondant présent à l'état naturel ou à une partie dudit allergène, mais ayant des effets secondaires réduits. La présente invention fournit en outre des séquences d'acides nucléiques codant pour les peptides de la présente invention. Des procédés de traitement ou de diagnostic de sensibilité au pollen de cèdre du Japon chez un sujet et des compositions thérapeutiques comprenant un ou plusieurs peptides de la présente invention sont également décrits. La présente invention concerne en outre des allergènes protéiques et des séquences d'acides nucléiques Jun v I et Jun s I codant pour des allergènes Jun s I et Jun v I. Jun s I et Jun v I sont des allergènes protéiques qui entrent immunologiquement en réaction croisée avec Cry j I.
PCT/US1993/000139 1991-07-12 1993-01-15 Proteines et peptides allergenes tires du pollen du cedre du japon WO1994001560A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
EP93903013A EP0659214A1 (fr) 1992-09-01 1993-01-15 Proteines et peptides allergenes tires du pollen du cedre du japon
JP50326994A JP4102432B2 (ja) 1992-09-01 1993-01-15 杉花粉由来のアレルゲン性蛋白質及びペプチド
AU34384/93A AU3438493A (en) 1992-07-10 1993-01-15 Allergenic proteins and peptides from japanese cedar pollen
KR1019950700826A KR950703058A (ko) 1992-09-01 1995-03-02 일본 삼목 꽃가루로 부터의 알레르겐 유발성 단백질 및 펩타이드(allergenic proteins and peptides from japanese cedar pollen)
US08/467,023 US6090386A (en) 1991-07-12 1995-06-06 T cell peptides of the CRX JII allergen
US09/240,203 US6982326B1 (en) 1991-07-12 1999-01-29 Allergenic proteins and peptides from Japanese cedar pollen
US10/931,260 US8540999B2 (en) 1991-07-12 2004-08-30 Allergenic proteins and peptides from Japanese cedar pollen

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US72913491A 1991-07-12 1991-07-12
US73045291A 1991-07-15 1991-07-15
PCT/US1992/005661 WO1993001213A1 (fr) 1991-07-12 1992-07-10 Proteines peptides allergeniques provenant du pollen du cedre japonais
US93899092A 1992-09-01 1992-09-01
US07/938,990 1992-09-01

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US97517992A Continuation-In-Part 1991-07-12 1992-11-12

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US97517992A Continuation-In-Part 1991-07-12 1992-11-12
US22624894A Continuation-In-Part 1991-07-12 1994-04-08

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Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995027786A1 (fr) * 1994-04-08 1995-10-19 Immulogic Pharmaceutical Corporation Formulations pharmaceutiques utilisees dans le traitement de la pollinose du cedre du japon
WO1996006630A1 (fr) * 1994-08-26 1996-03-07 The Regents Of The University Of California Procedes et compositions permettant de moduler une reponse des cellules t
EP0700929A2 (fr) * 1994-09-10 1996-03-13 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Peptides dérivés de allergènes du pollen de cèdre et leur applications
WO1997032600A1 (fr) * 1996-03-10 1997-09-12 Meiji Milk Products Co., Ltd. Agent immunotherapeutique a base peptidique pour le traitement des allergies
US5874401A (en) * 1993-12-27 1999-02-23 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Cedar pollen protein and use thereof in treating, preventing, and diagnosing pollenosis
EP0960887A1 (fr) * 1996-06-14 1999-12-01 Meiji Milk Products Company Limited PEPTIDE ANTIGENE Ly
US6090386A (en) * 1991-07-12 2000-07-18 Griffith; Irwin J. T cell peptides of the CRX JII allergen
WO2002072833A1 (fr) * 2001-03-09 2002-09-19 Universidad Complutense De Madrid Clonage de l'adn complementaire codant pour cup s 1, allergene majoritaire de cupressus sempervirens
EP1369483A1 (fr) * 2002-06-04 2003-12-10 BIOMAY Produktions- und Handels- Aktiengesellschaft Allergène du pollen de l'armoise
US6737406B1 (en) 1996-03-21 2004-05-18 Circassia, Ltd. Cryptic peptides and method for their identification
US7025964B1 (en) 1996-11-13 2006-04-11 Meiji Dairies Corporation Peptide-based immunotherapeutic agent
KR100562821B1 (ko) * 1996-06-14 2006-08-04 메이지 데어리즈 코포레이션 T세포에피토프펩티드
JP2007056036A (ja) * 2006-10-23 2007-03-08 Sankyo Co Ltd ペプチド及びその用途
JP2007091745A (ja) * 2006-10-23 2007-04-12 Sankyo Co Ltd ペプチド及びその用途
EP1997899A1 (fr) 1998-07-17 2008-12-03 Bayer BioScience N.V. Procédé et moyens pour moduler la mort cellulaire programmée dans des cellules eucaryotes
EP2025756A1 (fr) 2003-11-18 2009-02-18 Bayer BioScience N.V. Insertion d'ADN ciblée améliorée dans des plantes
EP2267138A2 (fr) 1998-04-08 2010-12-29 Commonwealth Scientific and Industrial Research Organization Procédés et moyens d'obtention de phénotypes modifiés
EP2278017A1 (fr) 2002-02-26 2011-01-26 Syngenta Limited Procédé de production séléctive des plantes stérile male ou femelle
US8491910B2 (en) 2008-08-15 2013-07-23 Circassia Limited Vaccine comprising AMB A 1 peptides for use in the treatment of ragweed allergy
US8753644B2 (en) 2009-02-05 2014-06-17 Circassia Limited Grass peptides for vaccine
US8821887B2 (en) 2008-08-15 2014-09-02 Circassia Limited T-cell antigen peptide from allergen for stimulation of IL-10 production
US9017689B2 (en) 2010-02-15 2015-04-28 Circassia Limited Peptides for vaccine against birch allergy

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993001213A1 (fr) * 1991-07-12 1993-01-21 Immulogic Pharmaceutical Corporation Proteines peptides allergeniques provenant du pollen du cedre japonais

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993001213A1 (fr) * 1991-07-12 1993-01-21 Immulogic Pharmaceutical Corporation Proteines peptides allergeniques provenant du pollen du cedre japonais

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
FEBS LETTERS. vol. 239, no. 2, November 1988, AMSTERDAM NL pages 329 - 332 TANIAI ET AL. 'N-terminal amino acid sequence of a major allergen of Japanese cedar pollen (Cry j I)' cited in the application *
PATENT ABSTRACTS OF JAPAN vol. 13, no. 419 (C-637)(3767) 18 September 1989 *
Section Ch, Week 8742, Derwent Publications Ltd., London, GB; AN 87-294838 *

Cited By (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6090386A (en) * 1991-07-12 2000-07-18 Griffith; Irwin J. T cell peptides of the CRX JII allergen
US5874401A (en) * 1993-12-27 1999-02-23 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Cedar pollen protein and use thereof in treating, preventing, and diagnosing pollenosis
WO1995027786A1 (fr) * 1994-04-08 1995-10-19 Immulogic Pharmaceutical Corporation Formulations pharmaceutiques utilisees dans le traitement de la pollinose du cedre du japon
WO1996006630A1 (fr) * 1994-08-26 1996-03-07 The Regents Of The University Of California Procedes et compositions permettant de moduler une reponse des cellules t
EP0700929A2 (fr) * 1994-09-10 1996-03-13 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Peptides dérivés de allergènes du pollen de cèdre et leur applications
EP0700929A3 (fr) * 1994-09-10 1999-09-01 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Peptides dérivés de allergènes du pollen de cèdre et leur applications
US6719976B1 (en) 1996-03-10 2004-04-13 Meiji Milk Products Co., Ltd. Peptide-based immunotherapeutic agent for treating allergic diseases
WO1997032600A1 (fr) * 1996-03-10 1997-09-12 Meiji Milk Products Co., Ltd. Agent immunotherapeutique a base peptidique pour le traitement des allergies
CN1330377C (zh) * 1996-03-10 2007-08-08 明治乳业株式会社 用于治疗变态反应疾病的基于肽的免疫治疗剂
KR100487456B1 (ko) * 1996-03-10 2005-11-25 메이지 데어리즈 코포레이션 알레르기질환에대한펩티드면역치료제
US6737406B1 (en) 1996-03-21 2004-05-18 Circassia, Ltd. Cryptic peptides and method for their identification
CN102286077A (zh) * 1996-06-14 2011-12-21 明治乳业株式会社 T细胞表位肽
EP0960887A1 (fr) * 1996-06-14 1999-12-01 Meiji Milk Products Company Limited PEPTIDE ANTIGENE Ly
US7407657B2 (en) 1996-06-14 2008-08-05 Meiji Dairies Corporation T-cell epitope peptides
US7547440B2 (en) 1996-06-14 2009-06-16 Meiji Dairies Corporation T-cell epitope peptides
EP0960887A4 (fr) * 1996-06-14 2002-09-18 Meiji Milk Prod Co Ltd PEPTIDE ANTIGENE Ly
US7112329B1 (en) 1996-06-14 2006-09-26 Meiji Milk Products Co. Ltd. T cell epitope peptide
KR100562821B1 (ko) * 1996-06-14 2006-08-04 메이지 데어리즈 코포레이션 T세포에피토프펩티드
US7025964B1 (en) 1996-11-13 2006-04-11 Meiji Dairies Corporation Peptide-based immunotherapeutic agent
EP2267139A2 (fr) 1998-04-08 2010-12-29 Commonwealth Scientific and Industrial Research Organization Procédés ét moyens d'obtention de phénotypes modifies
EP2267138A2 (fr) 1998-04-08 2010-12-29 Commonwealth Scientific and Industrial Research Organization Procédés et moyens d'obtention de phénotypes modifiés
EP3214177A2 (fr) 1998-04-08 2017-09-06 Commonwealth Scientific and Industrial Research Organisation Procédés et moyens pour obtenir des phénotypes modifiés
EP1997899A1 (fr) 1998-07-17 2008-12-03 Bayer BioScience N.V. Procédé et moyens pour moduler la mort cellulaire programmée dans des cellules eucaryotes
WO2002072833A1 (fr) * 2001-03-09 2002-09-19 Universidad Complutense De Madrid Clonage de l'adn complementaire codant pour cup s 1, allergene majoritaire de cupressus sempervirens
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