WO1995006122A2 - Allergenes recombines d'alternaria alternata - Google Patents

Allergenes recombines d'alternaria alternata Download PDF

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Publication number
WO1995006122A2
WO1995006122A2 PCT/AT1994/000121 AT9400121W WO9506122A2 WO 1995006122 A2 WO1995006122 A2 WO 1995006122A2 AT 9400121 W AT9400121 W AT 9400121W WO 9506122 A2 WO9506122 A2 WO 9506122A2
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WO
WIPO (PCT)
Prior art keywords
recombinant
allergens
gly
ala
alta22
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PCT/AT1994/000121
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German (de)
English (en)
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WO1995006122A3 (fr
Inventor
Gernot Achatz
Hannes Oberkofler
Birgit Simon
Andrea Unger
Erich Lechenauer
Reinhold Hirschwehr
Christoph Ebner
Dietrich Kraft
Hans-Jörg PRILLINGER
Michael Breitenbach
Original Assignee
Biomay Produktions- Und Handelsgesellschaft M.B.H.
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 Biomay Produktions- Und Handelsgesellschaft M.B.H. filed Critical Biomay Produktions- Und Handelsgesellschaft M.B.H.
Priority to EP94923587A priority Critical patent/EP0714442A1/fr
Priority to JP7507226A priority patent/JPH09503654A/ja
Priority to CA002170355A priority patent/CA2170355A1/fr
Priority to AU73772/94A priority patent/AU7377294A/en
Publication of WO1995006122A2 publication Critical patent/WO1995006122A2/fr
Publication of WO1995006122A3 publication Critical patent/WO1995006122A3/fr
Priority to NO960748A priority patent/NO960748L/no
Priority to FI960882A priority patent/FI960882A/fi

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/37—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from fungi
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Definitions

  • the invention relates to recombinant DNA molecules which code for polypeptides which have the antigenicity of the allergens Alta53, Alta22 and Altall, or for peptides which have at least one epitope of these allergens.
  • allergens of Alternaria alternata lead to a pathological immune response with an overshoot of IgE antibodies in allergy sufferers from fungi.
  • recombinant allergens or immunogenic partial peptides can also be used for in vivo or in vitro induction of an immune tolerance or anergy of T lymphocytes.
  • IgE antibodies which contact effector cells (mast cells of the mucous membrane and connective tissue type as well as basophilic granulocytes of the blood) with their Fc part via receptors and, in the event of allergen contact, release inflammatory substances (histamine, heparin , Arachidonic acid metabolites etc.) (Roitt 1991, Klein 1990).
  • IgE antibodies are formed by B lymphocytes, which are stimulated to secrete the antibodies by soluble substances (lymphokines) that are secreted by activated T lymphocytes (Parronchi et al. 1991). At the beginning of every immune response there are cells that actively phagocytize the existing antigen.
  • these cells are also called "feeding cells”. These are dendritic cells but also monocytes that differentiate into macrophages at a later stage. All of these cells have the ability of DIAPEDESE, which enables them to leave the blood system and penetrate into body cavities, etc. The main part of the antigen destruction is carried by the macrophages. After phagocytosis, they break down the antigen into highly immunogenic peptides (average size approx. 15 amino acids) and present them together with the MHC proteins (major histocompatibility) expressed on the macrophages, the T-lymphocytes. The central role of T lymphocytes is underlined at this point.
  • IgE-related allergies e.g. also allergies to fungal spores, treated by hyposensitization (Bousquet et al. 1991).
  • This therapy consists in the supply of allergen extracts in the form of injections or oral application in aqueous form as drops in increasing doses until a maintenance dose over several years is reached.
  • the result of this therapy is tolerance towards the allergens used, which is reflected in a decrease in the symptoms of the disease (Birkner et al. 1990).
  • the problem with this type of treatment lies in the large number of side effects that it causes.
  • Hyposensitization therapy has seen cases of anaphylactic shock during treatment. The problem here is the difficulty in standardizing the fungal protein isolates. If allergen-derived but not anaphylactic peptides are used, higher doses could be administered risk-free, which can lead to a significant improvement in hyposensitization.
  • Alternaria alternata is one of the most important allergy-causing fungi today. Yunginger et al. (1989) characterized the first allergenic fraction and isolated the first allergenic protein Altai. A big problem with Alternaria alternata is the range of variation of the fungus: Variations in the protein pattern but also variable potency of the triggering of allergies have been described many times. Nyholm et al. (1983) showed that Agl and Alt-1 are the same allergen, but that the protein can be varied in different strains of Alternaria alternata. The review article by Budd (1986) describes the isolation of the allergenic protein Alt-1, now Altal. Complete cDNA sequences of allergenic proteins from Alternaria alternata have not been published to date.
  • DNA molecules of the kind mentioned above which have nucleic acid sequences which homologously match sequences 1, 3-5, 7-9 and 12 and 13, or parts of these sequences, or nucleic acid sequences which correspond to hybridize said sequences under stringent conditions.
  • the DNA molecules can also have nucleic acid sequences which can be derived from the aforementioned sequences by degeneration.
  • Alternaria alternata (Prof. Windisch Berlin collection: 08-0203) was grown on solid medium (2% glucose, 2% peptone, 1% yeast extract).
  • solid medium 2% glucose, 2% peptone, 1% yeast extract.
  • the mushroom mat was removed after 3 days of growth at 28 ° C. and broken up with liquid nitrogen.
  • the extracted proteins were separated on a denaturing polyacrylamide gel, which was then blotted, incubated with patient serum and detected with 125 I-labeled anti-human IgE. Expressed in percentages, the patients reacted to the allergenic proteins as follows:
  • Alta53 is a major allergen
  • Alta22 and Alta11 a minor allergen
  • FIG. 1 shows an overview of the patient spectrum available for cloning the allergens described.
  • the picture shows a 12.5% polyacrylamide gel.
  • the patients with the numbers 35 and 40 (these are also the patients who were used for the later screening) show bands in the order of magnitude of 53 kD, 22 kD and l lKD.
  • 1 shows a Western blotting of a 12.5% polyacrylamide gel after separation of Alternaria alternata protein extract; Incubation with sera from different patients; Detection with 125 I-labeled anti human IgE.
  • RNA was obtained from self-grown mushroom material using the acid guanidium phenol extraction method.
  • poly (A) plus enrichment was carried out with oligo (dT) cellulose from Bschreibinger.
  • the cDNA synthesis (1st and 2nd strand) was carried out as described in the manual of the Lambda ZAP system from Stratagene.
  • the cDNA was then provided (3 'side) with EcoRI and (5' side) with Xbal linkers, ligated into predigested Lambda-ZAP arms and packaged.
  • the primary bank titer was 900,000 clones.
  • the expression bank was screened by incubating the "lifted" phage plaques with a sera mixture from 2 patients who were known by western blotting to cover the spectrum of the detected antigens. The detection was again carried out using anti-human IgE RAST antibody from Pharmacia. After secondary and tertiary screening, 150 positive clones remained. With the help of a helper phage, the ready-to-sequence bluescript vector was excised from 12 clones with cDNA (implementation as in the manual of the Lambda ZAP kit). Restriction digests of the excised plasmids showed (EcoRI-Xbal double digestion) 3 different insert types. These 3 clones were sequenced using the Sanger method (Sanger 1977). d) Expression of the Alta53, Alta22 and Alta11 cDNAs as ⁇ -galactosidase fusion protein
  • FIGS. 3 and 4 show the recombinant ⁇ -galactosidase fusion proteins after incubation with patient serum and detection with iodine-labeled anti-human IgE.
  • the ⁇ -galactosidase portion of the fusion protein is 36 amino acids, which is equivalent to a molecular weight of 3800 daltons. Taking this "enlargement" of the allergenic protein into account, the following FIGS. 3 and 4 can also be seen.
  • Lanes (clones) 1, 2, 4, 5, 6, 7 show the recombinant fusion protein Altal 1
  • lanes 3 and 12 show the recombinant fusion protein Alta22
  • lanes 8 and 10 show the recombinant Alta53 which has increased by the amount of fusion.
  • the derived amino acid sequence of the allergens provides the prerequisite for the prediction of B and T cell epitopes using suitable computer programs.
  • specific T and B cell epitopes can be defined that have the ability, e.g. To stimulate T lymphocytes and stimulate proliferation, but also to put the cells (at a precisely defined dose) into a state of tolerance or non-reactivity (anergy) (Rothbard et al. 1991).
  • the specific epitopes are given in the description of the recombinant protein in separate figures.
  • the search for B cell epitopes was carried out using the GCG program (Genetics Computer Group) "PROTCALC", which was expanded by the working group around Prof. Modrow with essential parameters. The determination is based on a weighing of the parameters of hydrophilicity (Kyte-Doolittle), secondary structure (Chou-Fasman), surface localization (Robson-Garnier) and flexibility, whereby the antigenicity of partial peptides is calculated.
  • the principle of the T cell epitope prediction was in principle based on the
  • Sequence 1 shows the complete cDNA sequence of Alta53 starting with the start ATG.
  • the length of the cDNA is 1488 bp, which corresponds to a calculated molecular weight of 53543 daltons.
  • the observed band in the Western blot at 53 kD thus correlates in molecular weight with the cloned and sequenced allergen. According to previous analysis, the mature protein should not be preceded by a signal peptide.
  • DNA sequence 1488 bp ATGACATCTGTA ... CTGTTCGGTTAA linear Homology searches with Alta53 in the SWISSPROT protein database showed that Alta53, like Clah53, is an aldehyde dehydrogenase.
  • the following sequence 2 shows a pairwise alignment between Alta53 and Clah53.
  • the identity (identical amino acids) of the two proteins (allergens) among each other is 78%.
  • the degree of homology is as high as 86%.
  • the NAD-dependent ALDH is the main enzyme that is involved in the oxidation of acetaldehyde, a primary product of alcohol metabolism, in humans. Isoenzymes are often found here (Harada et al. 1982). In humans, for example, the isoenzyme ALDH I is found in mitochondria, ALDH II in the cytoplasm. Interestingly, the absence of ALDH I is not uncommon in Asians (Harada et al. 1982). The deficiency of ALDH I results in a high level of acetaldehyde, which manifests itself as a so-called "flushing syndrome", as well as other vasomotor symptoms after alcohol consumption. The loss of isoenzyme can be attributed to a mutation that changes the structure of the native protein (Hsu et al. 1987). The relationship between ALDH and allergy triggering is not yet known.
  • Sequence 3 shows the areas with high antigenic index identified by computer search. These areas represent highly potent B cell epitopes.
  • Sequence 4 shows the amphipathic helices determined with the aid of the computer program and flanked by hydrophilic areas. Such areas, with a score higher than 10, represent possible ones
  • T cell epitopes are calculated from the amino acid positions of the midpoints, which are flanked at the N-terminal by a lysine (K) and C-terminal by a proline (P). Potential T cell epitopes are only present if the "score index" is greater than 10.
  • Sequence 5 shows the complete cDNA sequence of Altal 1 and the amino acid sequence derived from it.
  • the open reading frame comprises 342bp or 114 amino acids.
  • the calculated molecular weight is 11127 daltons and thus corresponds to the UkD-sized antigenic protein, which is recognized by 10.3% of patients in western emblot.
  • ribosomal protein P2 Homologies to the ribosomal protein P2.
  • This ribosomal protein is at the Formation of the large subunit of the ribosomes involved. This means that homology to Clah11, the counterpart of Alta11 in Cladosporium herbarum, is inevitable. The identities and homologies between Alta11 and Clah11 are evident from the following sequence 6. The identity of the two proteins is 74%, the degree of homology increases to 84%, which undoubtedly indicates a similar function of these two proteins.
  • Acidic ribosomal proteins (such as P0, P1 and P2) from various organisms have been analyzed using a variety of techniques. One differentiates
  • a proteins are the large number of hydrophobic amino acids. They can therefore be relatively easily dissociated from the ribosome (50% ethanol and high
  • L7 / L12 protein from Escherichia coli.
  • the eukaryotic homologues are
  • Proteins P1 and P2 which, like the L7 / L12 protein, have the elongation factor
  • the C-terminal sequence contains an epitope, which of
  • the following sequence 8 shows the calculated T cell epitopes and represents the amino acids in the 1-letter code.
  • T cell epitopes are calculated from the amino acid positions of the midpoints, which are flanked N-terminally by a lysine (K), C-terminally by a proline (P). Potential T cell epitopes are only present if the "score index" is greater than 10.
  • Sequence 9 shows the complete cDNA sequence of Alta22.
  • the protein primary sequence derived therefrom can also be seen from the sequence.
  • the open reading frame of the allergenic protein is 615 bp, which corresponds to an amino acid length of 205 amino acids.
  • the calculated molecular weight of the recombinant protein is 22041 daltons. According to previous analysis, the mature protein is not preceded by a signal sequence.
  • ORGANISM Alternaria alternans
  • ORGANISM Alternaria alternans
  • YCP4 The sequence or the open reading frame of YCP4 was localized and published as part of the yeast genome project on chromosome 3 of Saccharomyces cerevisiae (Biteau et al. 1992). Disruption of YCP4 showed according to Biteau et al. (1992) no phenotype. However, refined phenotype analyzes carried out suggest that yeast YCP4 may have a function as a heat shock protein. This experiment also shows how important Saccharomyces cerevisiae can be for the functional analysis of allergens. The ease of transformability combined with sophisticated methods of molecular genetics make it possible to disrupt genes in yeast and to analyze the resulting phenotype.
  • Alta22 also has its homologous partner in Cladosporium herbarum.
  • sequence 11 shows a "multiple sequence alignment" between the yeast YCP4 and the allergens Alta22 and Clah22.
  • the B cell epitopes found with computer support can be seen in the next sequence 12.
  • Sequence 13 shows the calculated T cell epitopes. Amphipathic areas with a score less than 10 are assumed to be irrelevant.
  • T cell epitopes are calculated from the amino acid positions of the midpoints, which are flanked at the N-terminal by a lysine (K) and C-terminal by a proline (P). Potential T cell epitopes are only present if the "score index" is greater than 10.
  • Anti-P autoantibody production requires P1 / P2 as immunogens but is not driven by exogenous self-antigen in mrl mice.
  • MHC molecules as peptide reeeptors.
  • Human acidic ribosomal phosphoproteins P0, P1 and P2 analysis of cDNA clones, in vitro synthesis and assembly.

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Abstract

L'invention se rapporte à des molécules d'ADN recombinées qui codent pour des polypeptides qui possèdent l'antigénicité des allergènes Alta53, Alta22 et Alta11 ou pour des peptides présentant au moins un épitope de ces allergènes. Ces molécules sont caractérisées en ce qu'elles présentent des séquences d'acide nucléique qui concordent, de façon homologue, avec les séquences 1, 3-5, 7-9, 12 et 13, ou avec des domaines partiels de ces séquences, ou des séquences d'acide nucléique hybridées avec les séquences d'acide nucléique précitées dans des conditions sévères.
PCT/AT1994/000121 1993-08-27 1994-08-24 Allergenes recombines d'alternaria alternata WO1995006122A2 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
EP94923587A EP0714442A1 (fr) 1993-08-27 1994-08-24 Allergenes recombines d'alternaria alternata
JP7507226A JPH09503654A (ja) 1993-08-27 1994-08-24 組み換えアルタナリアアルタネイタ（Ａｌｔｅｒｎａｒｉａａｌｔｅｒｎａｔａ）アレルゲン
CA002170355A CA2170355A1 (fr) 1993-08-27 1994-08-24 Allergenes d'alternaria alternaria recombinants
AU73772/94A AU7377294A (en) 1993-08-27 1994-08-24 Recombinant alternaria alternata allergenes
NO960748A NO960748L (no) 1993-08-27 1996-02-23 Rekombinante Alternaria alternata allergener
FI960882A FI960882A (fi) 1993-08-27 1996-02-26 Alternaria alternata -yhdistelmäallergeeneja

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ATA1726/93 1993-08-27
AT0172693A AT400723B (de) 1993-08-27 1993-08-27 Rekombinante alternaria alternata allergene

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WO1995006122A2 true WO1995006122A2 (fr) 1995-03-02
WO1995006122A3 WO1995006122A3 (fr) 1995-07-13

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JP (1) JPH09503654A (fr)
AT (1) AT400723B (fr)
AU (1) AU7377294A (fr)
CA (1) CA2170355A1 (fr)
FI (1) FI960882A (fr)
NO (1) NO960748L (fr)
WO (1) WO1995006122A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000026360A1 (fr) * 1998-11-03 2000-05-11 Adherex Technologies Inc. Composes et methodes permettant de moduler des fonctions induites par les claudines
US6610649B2 (en) 1996-09-27 2003-08-26 Creative Peptides Sweden Ab Insulin C-peptides
US6723700B1 (en) 1998-11-03 2004-04-20 Adherex Technologies, Inc. Compounds and methods for modulating claudin-mediated functions
WO2013179043A1 (fr) * 2012-06-01 2013-12-05 Circassia Limited Peptides d'alternaria

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
D. KRAFT AND M. SEHON 'Mol. Biol. Immunol. Allergens' 1993 , CRC , BOCA RATON R. BUSH AND H. SANCHEZ: Partial cDNA sequence of an Alternaria allergen siehe Seite 271 - Seite 273 *
EMBO JOURNAL, Bd. 8, 1989 Seiten 1935-1938, H. BREITENEDER 'The gene coding for the major birch pollen allergen BetvI, is highly homologous to a pea disease resistance response gene' *
JOURNAL OF BIOLOGICAL CHEMISTRY, Bd. 266, Nr. 2, 15.Januar 1991 MD US, Seiten 1204-1210, A. SILVANOVICH ET AL 'Nucleotide sequence and analysis of three cDNAs coding for Poa p IX isoallergens of Kentucky Bluegrass pollen' *
JOURNAL OF IMMUNOLOGY, Bd. 138, Nr. 7, 1.April 1987 Seiten 2213-2229, H. MARGALIT ET AL 'Prediction of immunodominant helper T cell antigenic sites from the primary sequence' in der Anmeldung erw{hnt *
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF USA, Bd. 80, M{rz 1983 WASHINGTON US, Seiten 1194-1198, R. YOUNG AND R. DAVIS 'Efficient isolation of genes by using antibody probes' *
THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Bd. 83, Nr. 1, 1989 Seite 292 I. OLSON ET AL 'Affinity purification of a major Alternaria anitgen using a monoclonal antibody' *
THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Bd. 89, Nr. 1, 1992 Seite 283 C. BARNES ET AL 'Comparison of proteins from four strains of Alternaria using two-dimensional electrophoresis' *
THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Bd. 89, Nr. 1, 1992 Seite 283 I. CURRAN ET AL 'Purification and characterization of a low molecular weight antigen from Alternaria alternata' *
THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Bd. 89, Nr. 1, 1992 Seite 283 J. FOLGERT ET AL 'Characterization of an Alternaria allergen' *
THE JOURNAL OF ALLERGY AND CLINICAL IMMUNUNOLOGY, Bd. 89, Nr. 1, Januar 1992 Seite 241 H. SANCHEZ ET AL 'cDNA sequence of an Alternaria allergen' *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6610649B2 (en) 1996-09-27 2003-08-26 Creative Peptides Sweden Ab Insulin C-peptides
WO2000026360A1 (fr) * 1998-11-03 2000-05-11 Adherex Technologies Inc. Composes et methodes permettant de moduler des fonctions induites par les claudines
US6723700B1 (en) 1998-11-03 2004-04-20 Adherex Technologies, Inc. Compounds and methods for modulating claudin-mediated functions
US6756356B2 (en) 1998-11-03 2004-06-29 Adherex Technologies, Inc. Compounds and methods for modulating claudin-mediated functions
US6830894B1 (en) 1998-11-03 2004-12-14 Adherex Technologies, Inc. Compounds and methods for modulating claudin-mediated functions
WO2013179043A1 (fr) * 2012-06-01 2013-12-05 Circassia Limited Peptides d'alternaria
GB2517871A (en) * 2012-06-01 2015-03-04 Circassia Ltd Alternaria peptides

Also Published As

Publication number Publication date
CA2170355A1 (fr) 1995-03-02
AU7377294A (en) 1995-03-21
NO960748L (no) 1996-04-24
FI960882A (fi) 1996-04-24
AT400723B (de) 1996-03-25
FI960882A0 (fi) 1996-02-26
ATA172693A (de) 1995-07-15
NO960748D0 (no) 1996-02-23
EP0714442A1 (fr) 1996-06-05
JPH09503654A (ja) 1997-04-15
WO1995006122A3 (fr) 1995-07-13

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