WO2004104047A1 - Hypoallergenic variants of the parietaria judaica major allergens, uses thereof and compostitions comprising them - Google Patents
Hypoallergenic variants of the parietaria judaica major allergens, uses thereof and compostitions comprising them Download PDFInfo
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- WO2004104047A1 WO2004104047A1 PCT/IT2004/000284 IT2004000284W WO2004104047A1 WO 2004104047 A1 WO2004104047 A1 WO 2004104047A1 IT 2004000284 W IT2004000284 W IT 2004000284W WO 2004104047 A1 WO2004104047 A1 WO 2004104047A1
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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
- C07K14/415—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from plants
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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
- A61K39/35—Allergens
- A61K39/36—Allergens from pollen
-
- 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
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- 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
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention concerns hypoallergenic protein molecules derived from the Parietariajudaica major allergens, uses and compositions thereof.
- the allergic reaction also known as type I hypersensitivity reaction, is caused by an IgE-mediated response to normally harmless environmental antigens present in animal dander, dust mites and pollen. Symptoms include wheals and skin eruptions, rhinoconjunctivitis, difficulty in breathing and other more severe conditions such as asthma and anaphylaxis.
- Respiratory allergies may be classified as seasonal or perennial, depending on the period of the year in which they appear.
- seasonal respiratory allergies the allergens causing the disorder are present in the pollen of plants that bloom chiefly in the spring.
- the pollen suspended in the atmosphere is inhaled and reaches the mucous membrane of the respiratory tract where the protective envelope surrounding the pollen is dissolved by the enzymes and moisture present in the mucosal secretion, thus releasing the proteins contained in the envelope.
- the most common allergenic plant species belong to several large families: Fagaceae, Urticaceae, Oleaceae, composites and Graminaceae. In continental Italy, the
- Graminaceae family is the main cause of allergic reactions, whereas in the Mediterranean area the main allergenic plant is Parietaria judaica (Pj).
- the genus Parietaria belongs to the Urticaceae family and includes five species which ranked by allergic importance are.
- CIE and CRIE biochemical methods
- the range of the molecular weight of the allergens is from 10 to 80 kDa, and those with a weight from 10 to 14 kDa react with all sera of allergic subjects, suggesting that the main allergens can be found in this range (2, 3).
- the recombinant DNA technique to isolate the Pj major allergens allowed the isolation and characterization of the major allergens, Par j 1 and Par j 2, and several of their isoforms (4). From Par j 1 two variants were isolated, designated Par j
- Par j 1.0102 has an insert of 794 nucleotides, a deduced amino acid sequence containing 176 amino acids with a molecular weight of 18.450 Da.
- the NH 2 -terminal sequence has the characteristic amino acid sequence of glycosylated protein signal sequences.
- the mature protein has 139 amino acids and a molecular weight of 14.476 Da (Fig. 1, panel a).
- Sequence analysis of the Par j 1.0201 clone showed an insert of 637 nucleotides, an amino acid sequence of 139 amino acids, and a molecular weight of 14.400 Da. It also contains an amino terminal region with signal sequence characteristics.
- the mature protein contains 102 amino acids and has a molecular weight of 10.677 Da.
- Par j 1.201 may be considered a shorter variant of Par j 1.0102 (5, 6).
- the Par j 2 clone isolated from a cDNA gene library, contains an insert of 622 nt with a correct reading phase of 133 amino acids and a signal peptide of 31 amino acids.
- the mature protein contains 102 amino acids and has a molecular weight of 11.344 Da (Fig. 1, panel C).
- Par j 1 and Par j 2 are two independent allergens, as demonstrated by cross-reactivity experiments (7).
- the IgE binding in the 10 — 14 kDa region of the Pj pollen is completely inhibited, suggesting that only these two allergens are present in this region and that together they are capable of inhibiting the majority of specific IgE against Pj allergens (7).
- the administration of the allergen in toto carries the risk of side effects that may also cause anaphylactic shock.
- one of the principal objectives is to characterize and to develop alternative molecules with fewer side effects, i.e. molecules that do not interact with IgE.
- the modification of native allergens in an attempt to generate molecules with reduced risk of anaphylaxis has been proposed by March and co-workers, who suggested polymerizing crude extracts with formaldehyde or gluteraldehyde (11). Clinical trials demonstrated the efficacy of these modified molecules, but they still had all the drawbacks described above regarding the difficulty of accurately standardizing the extracts.
- Patent application WO 02/20790 concerns the variants of the family of ns-LTP allergens, to which the allergens of the present invention belong, with a reduced ability to form disulfide bridges.
- Patent application WO 02/22674 concerns that hypoallergenic variants of the major allergen Par j 2 in which lysine residues are substituted or deleted.
- both documents of previous technology concern variants of a specific allergen and do not produce a molecule engineered to contain multimers of single allergens and/or regions deriving from different allergens that can be advantageously used as a single hypoallergenic principle.
- the multimer protein molecule of the invention also contains at least a third sequence of one of the Parietariajudaica major allergens Par j 1 or Par j 2.
- the sequence of the major allergen Par j 1 is substantially
- the sequence of the Parietariajudaica major allergen Par j 1 and/or of the major allergen Par j 2 is mutated in the amino acid region of loop 1, substantially comprised from amino acid 1 to 30 of Seq Id No. 1 and or Seq Id No. 3.
- a further object of the invention is a nucleic acid that encodes the multimer protein molecule of the invention.
- a further object of the invention is a recombinant vector for expression in prokaryotic cells, comprising, under the control of a suitable transcription promoter system, the nucleic acid of the invention.
- a further object of the invention is a recombinant vector for expression in eukaryotic cells, comprising, under the control of a suitable transcription promoter system, the nucleic acid of the invention.
- a further object of the invention is a multimer protein molecule according to the invention for medical use, preferably as a hypoallergenic.
- a further object of the invention is a pharmaceutical composition
- a pharmaceutical composition comprising an effective and acceptable amount of the multimer protein molecule according to the invention and suitable adjuvants and/or diluents.
- FIG. 1 Amino acid sequences of major allergen Par j 1 (A) (Seq Id. No. 1) and Par j 2 (C) (Seq Id No. 3). Sequence B shows the hypoallergenic derivative of Par j 1 mutated in the loop 1 region (Seq Id No. 2); sequence D shows the hypoallergenic derivative of Par j 2 in the loop 1 region (Seq Id No. 4); underlined amino acids show inserted mutations.
- A major allergen Par j 1
- C Par j 2
- Sequence B shows the hypoallergenic derivative of Par j 1 mutated in the loop 1 region (Seq Id No. 2)
- sequence D shows the hypoallergenic derivative of Par j 2 in the loop 1 region (Seq Id No. 4); underlined amino acids show inserted mutations.
- Figure 2 Schematic diagram of the three-dimensional model of Par j 1 illustrating the structure composed of four alpha helices typical of the ns-LTP family.
- Figure 3 Alignment of the amino acid sequences of Par j 1.0102 and Par j 2.0101 in relation to their three-dimensional structure. The numbers refer to the Par j 1.0102 sequence. Arrows indicate substituted amino acids.
- FIG. 4 Schematic diagram of plasmid constructs. The numbers indicate the position of the amino acids starting from the first methionine as expressed by the pQE30 and pQE31 expression vectors used for the expression of recombinant proteins. Added or substituted amino acids are indicated.
- Figure 5. ELISA test showing the ability of the Pj 1 loop and Pj2 loop mutants to bind to the human IgE as compared to respective wild-type molecules. The lines with black squares denote sera of Pj-allergic subjects; the line with white squares denotes the binding activity of serum from a non-allergic subject.
- Panels A — E show the amount of histamine released by the Pj 1 loop mutant and the Par j 1 wild-type molecule.
- Panels F — H indicate the amount of histamine released by the PjED and PjEDmut mutants compared with a mix containing an equimolecular quantity of the Par j 1 and Par j 2 allergens. Each panel represents one allergic patient.
- the values on the c-axis indicate the concentration of antigen in ⁇ g/ml.
- the values on the -axis express the percentage of released histamine compared with the total amount of histamine.
- Figure 7. ELISA test using the wild-type Par j 1 (Pjl) and Pjl loop molecules as antigens.
- the values on the -axis indicate the binding ability of the molecules compared with a polyclonal antibody against the Par j 1 molecule.
- FIG. 8 Histamine release assay of the Pj2 trimer mutant compared with an equimolecular amount of the monomer Par j 2 allergen.
- Panels A — D indicate the amounts of histamine released by each allergic patient.
- the ⁇ >axis indicates the antigen concentration expressed in ng/ml.
- the _y-axis expresses the percentage of released histamine compared with the total amount of histamine.
- FIG. 9 Histamine release profile of the heterotrimer mutant compared with Par j 1 and Par j 2 monomers.
- Panels A — C indicate the quantity of histamine released by each patient.
- the values on the ;c-axis indicate the antigen concentration expressed in ⁇ g/ml.
- the pQE30 prokaryote vector (Qiagen) was used.
- the vector is able to express recombinant proteins fused to a short histidine tail, in an inducible way by means of isopropyl-/3-D-thiogalactoside (IPTG).
- IPTG isopropyl-/3-D-thiogalactoside
- the histidine residues permit the purification of the recombinant protein by affinity chromatography.
- the P5 clone containing the processed version of Par j 1 (EMBL accession number X77414) underwent one cycle of DNA polymerase chain reaction (PCR) under the conditions: 94° C for 1 min, 52° C for 1 min, 72° C for 1 min for 30 cycles.
- PCR DNA polymerase chain reaction
- Parj 2 forward (5' CCTGGATCCGAGGAGGCTTGCGGG 3') (Seq Id No. 7) and Par j 2 reverse (5' GCGAAGCTTATAGTAACCTCTGAAAATAGT 3') (Seq Id No.
- DNA ligase enzyme according to various stoichiometric ratios.
- the reaction mixture was used to transform the bacterial strain Ml 5.
- the recombinant clones were isolated and the plasmid DNA was sequenced using the Sanger method.
- the resulting nucleotide sequence showed that the DNA fragment inserted in the pQE30 vector was identical to our previously published results.
- the point mutants of Par j 1 and Par j 2 were generated by PCR using as template the cDNA described above that encodes the wild-type versions of these allergens.
- the following oligonucleotides were used: Parj 1-fwd (5'-ATTGGATCCCAAGAAACCTGCGGGACTATG-3') (Seq Id No 9)
- LOOP 1 mut-rev (5 ' - AAACTGC AGC ACCCCgcTG ACGGCgCTgcCTCTTTCC-3 ') (Seq Id No.
- Par j 2 fwd (5'-GTGGGATCCGAGGAGGCTTGCGGGAAAGTGGTGCAG-3') (Seq Id No 11)
- Par j 2 mut-rev (5'-AAACTGCAGCACTCCgcCGACGGCgCCgcCTCCTCCC-3') (Seq Id No 12), to synthesize a DNA fragment encoding the first 30 amino acids of the Par j 2amino acid terminal in which the amino acids Lys23, Glu24, Lys27 were substituted with the neutral alanine amino acid.
- the generated DNA fragment was then digested at 5' and 3' with the restriction enzymes Bam HI and Pst I, respectively, and introduced into the Pj2 expression vector digested with the same restriction enzymes (bold letters denote the restriction enzyme sites used for cloning; lower case letters denote the substituted nucleotides for mutagenesis; see Fig. 1, panel E and Fig. 3, Fig. 4 for numbers and position of the amino acids).
- Pj2-rev (5'-CGCGGATCCATAGTAACCTCTGAAAATAGT-3') (Seq Id No. 14) and the Pj2 clone as a template and under the same PCR conditions: 94°C for 1 min, 52°C for 1 min, 72°C for 1 min for 30 cycles.
- the resulting fragment was then purified and digested with the Bam HI restriction enzyme and inserted in the Pj 1 plasmid previously digested with the same restriction enzyme.
- the recombinant plasmids containing a copy of the Par j 2 fragment inserted in the correct orientation were isolated and assayed for their ability to express stable recombinant multimer proteins (dimers Parj2-Parjl) (Fig. 4, PjED clone).
- two amino acids (G and S) were introduced at the level of the junction sites, without shifting the correct reading phase.
- the heterodimer containing a copy of each of the Par j 1 and Par j 1 allergens mutagenized in the loopl region was generated using a PCR strategy identical to that described for the formation of the Parj 1 -Parj2 heterodimer, modifying only the template used for PCR.
- the Pj2 loop clone was amplified using the Pj2-for and Pj2- rev oligonucleotides.
- the resulting fragment was then purified and digested with the restriction enzyme Bam HI and inserted in the Pjl loop plasmid previously digested with the same restriction enzyme.
- the plasmid vector pQE31 the DNA encoding the Par j 2 recombinant protein and the XLI blue bacterial strain of E. coli were used.
- the Par j 2 DNA was amplified by PCR using the following primers:
- Reverse Hind III 3'- CCTAAGCTTCTAATAGTAACCTCT-5' (Seq Id No. 20) and under the following conditions: 94°C for 1 min, 52°C for 1 min, 72°C for 1 min for
- the plasmid construction was digested with Sac I and Sal I enzymes. The linearized plasmid was then incubated with the DNA fragment containing the Par j 2 allergen after amplification by PCR using the direct Sac I and reverse Sal I primers. The recombinant clones were analyzed and controlled as described previously.
- the plasmid DNA containing the Par j 2 dimer was digested with Sal I and Hind III enzymes, and then incubated in a ligase reaction, with a DNA fragment containing the information for the Par j 2 amplified with the direct Sal I and reverse Hind III primers. It should be noted that in this clone a stop codon is inserted. Cloning is confirmed by sequencing the recombinant plasmid DNA.
- the lysate is then centrifuged at 14.000 rpm for 30 min, and the clarified lysate is loaded on a CM Sepharose (Pharmacia) column.
- the proteins are diluted using a discontinuous gradient of NaCl, and the fractions containing the protein of interest are dialyzed for 2 hours against a buffer containing 10 mM Na phosphate pH 7.4 and 1 M NaCl to allow the formation of the native three-dimensional structure.
- the recombinant proteins were then definitively purified using a His Trap column (Amersham) following the manufacturer's instructions.
- the diluted fractions were then analyzed on 16% polyacrylamid gel, and the fractions containing the recombinant protein were quantitatively evaluated by spectrophotometry after staining by the Bradford method. Lastly, the proteins were desalted using a Sephadex G-25 column (Pharmacia). The proteins produced by recombination technique were electrophorated on 16% SDS polyacrylamid gel. Their purity and concentration were determined by Coomassie
- the spontaneous release was calculated by incubating the sample in the presence of the dilution buffer.
- the percentage of released histamine was calculated as the percentage of histamine released after subtracting the percentage spontaneously released by the sample without stimulation.
- Par j 1 and Par j 2 are the two major players in allergic reaction and therefore represent two chief targets in the search for products to be used in specific immunotherapy for treating Pj allergy.
- These two independent allergens present similar characteristics in that they belong to the ns-LTP family.
- This family of plant proteins has been characterized at the structural level. All its components possess a highly compact structure comprising four alpha helices (see Fig. 2) brought together by eight cysteine residues that form four sulfur bridges in the order 4-52, 14-
- FIG. 2 Fig. 2, Fig. 3 have shown they can enormously influence the binding ability with human IgE.
- an ELISA analysis demonstrates a sharp reduction in IgE binding for Pjl loop and Pj2 loop mutants, reaching a level of activity comparable with that of the serum of a non-allergic patient.
- Figure 7 shows an ELISA analysis demonstrates a sharp reduction in IgE binding for Pjl loop and Pj2 loop mutants, reaching a level of activity comparable with that of the serum of a non-alle
- the Pj2 trimer mutant is composed of three pairs of head- to-tail linked Par j 2 allergen copies, as shown in Fig. 4.
- the molecule was studied in a histamine release test on four Pj-allergic subjects. All subjects presented a marked reduction in histamine release in that their activity was comparable to that of monomer Par j 2 (Fig. 8).
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Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
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AU2004240831A AU2004240831B2 (en) | 2003-05-20 | 2004-05-19 | Hypoallergenic variants of the Parietaria judaica major allergens, uses thereof and compostions comprising them |
CA002526275A CA2526275A1 (en) | 2003-05-20 | 2004-05-19 | Hypoallergenic variants of the parietaria judaica major allergens, uses thereof and compostitions comprising them |
EP04733904A EP1625167A1 (en) | 2003-05-20 | 2004-05-19 | Hypoallergenic variants of the parietaria judaica major allergens, uses thereof and compositions comprising them |
JP2006531025A JP4745237B2 (en) | 2003-05-20 | 2004-05-19 | Hypoallergenic variants of the major allergens of Parietaria judaika, their use and compositions containing them |
US10/557,586 US20060155116A1 (en) | 2003-05-20 | 2004-05-19 | Hypoallergenic variants of the parietaria judaica major allergens, uses thereof and compostitions comprising them |
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ITRM2003A000247 | 2003-05-20 | ||
IT000247A ITRM20030247A1 (en) | 2003-05-20 | 2003-05-20 | HYPOALLERGENIC VARIANTS OF MAJOR ALLERGENS |
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US (1) | US20060155116A1 (en) |
EP (1) | EP1625167A1 (en) |
JP (1) | JP4745237B2 (en) |
AU (1) | AU2004240831B2 (en) |
CA (1) | CA2526275A1 (en) |
IT (1) | ITRM20030247A1 (en) |
WO (1) | WO2004104047A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1712560A1 (en) * | 2005-04-15 | 2006-10-18 | Lofarma S.p.A. | Hypoallergenic proteins derived from the major allergen of parietaria judaica |
EP2007798A1 (en) * | 2006-04-12 | 2008-12-31 | Bial Industrial Farmaceutica, S.A. | Hypoallergenic chimeric proteins belonging to the lipid transfer family of parietaria judaica for use in the treatment of allergies |
WO2009115568A1 (en) * | 2008-03-19 | 2009-09-24 | Consiglio Nazionale Delle Ricerche | Anti-lps factor from parietaria judaica and methods of use thereof |
ITMI20091411A1 (en) * | 2009-08-04 | 2011-02-05 | Lofarma Spa | HYBRID PROTEIN HYPOALLERGENIC AND ITS USES |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ITRM20040103A1 (en) * | 2004-02-27 | 2004-05-27 | Consiglio Nazionale Ricerche | MELTING PROTEINS INCLUDING ALLERGENS OF THE NS-LTPS FAMILY, THEIR USES AND PHARMACEUTICAL COMPOSITIONS THAT INCLUDE THEM. |
Citations (3)
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WO2002020790A1 (en) * | 2000-09-11 | 2002-03-14 | Consiglio Nazionale Delle Ricerche | Parietaria judaica ns-ltp antigen variants, uses thereof and compositions comprising them |
WO2002022674A2 (en) * | 2000-09-12 | 2002-03-21 | Consiglio Nazionale Delle Ricerche | VARIANTS OF THE MAJOR ALLERGEN Par j 2 OF Parietaria judaica |
EP1219301A1 (en) * | 2000-12-28 | 2002-07-03 | SHAN-Beteiligungsgesellschaft m.b.H. | Vaccines containing hybrid polypeptides consisting of at least two different allergenic proteins |
-
2003
- 2003-05-20 IT IT000247A patent/ITRM20030247A1/en unknown
-
2004
- 2004-05-19 AU AU2004240831A patent/AU2004240831B2/en not_active Ceased
- 2004-05-19 CA CA002526275A patent/CA2526275A1/en not_active Abandoned
- 2004-05-19 US US10/557,586 patent/US20060155116A1/en not_active Abandoned
- 2004-05-19 EP EP04733904A patent/EP1625167A1/en not_active Ceased
- 2004-05-19 JP JP2006531025A patent/JP4745237B2/en not_active Expired - Fee Related
- 2004-05-19 WO PCT/IT2004/000284 patent/WO2004104047A1/en active Application Filing
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Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1712560A1 (en) * | 2005-04-15 | 2006-10-18 | Lofarma S.p.A. | Hypoallergenic proteins derived from the major allergen of parietaria judaica |
EP2007798A1 (en) * | 2006-04-12 | 2008-12-31 | Bial Industrial Farmaceutica, S.A. | Hypoallergenic chimeric proteins belonging to the lipid transfer family of parietaria judaica for use in the treatment of allergies |
JP2013233149A (en) * | 2006-04-12 | 2013-11-21 | Bial Industrial Farmaceutica Sa | Hypoallergenic chimeric protein belonging to lipid transfer protein family of parietaria judaica for use in treatment of allergy |
EP2007798B1 (en) * | 2006-04-12 | 2015-09-30 | Bial Industrial Farmacéutica, S.A. | Hypoallergenic chimeric proteins belonging to the lipid transfer family of parietaria judaica for use in the treatment of allergies |
JP2016104796A (en) * | 2006-04-12 | 2016-06-09 | ビアル インダストリアル ファーマキューティカ,エス.エー. | Hypoallergenic chimeric proteins belonging to lipid transfer family of parietaria judaica for use in allergy treatment |
US9522939B2 (en) | 2006-04-12 | 2016-12-20 | Bial Industrial Farmaceutica, S.A. | Hypoallergenic chimeric proteins belonging to the lipid transfer family of Parietaria judaica for use in the treatment of allergies |
WO2009115568A1 (en) * | 2008-03-19 | 2009-09-24 | Consiglio Nazionale Delle Ricerche | Anti-lps factor from parietaria judaica and methods of use thereof |
US8535680B2 (en) | 2008-03-19 | 2013-09-17 | Consiglio Nazionale Delle Ricerche | Anti-LPS factor from Parietaria judaica and methods of use thereof |
ITMI20091411A1 (en) * | 2009-08-04 | 2011-02-05 | Lofarma Spa | HYBRID PROTEIN HYPOALLERGENIC AND ITS USES |
EP2281836A1 (en) | 2009-08-04 | 2011-02-09 | LOFARMA S.p.A. | Hybrid proteins from Parietaria judaica major allergens and uses thereof |
Also Published As
Publication number | Publication date |
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EP1625167A1 (en) | 2006-02-15 |
JP4745237B2 (en) | 2011-08-10 |
ITRM20030247A0 (en) | 2003-05-20 |
US20060155116A1 (en) | 2006-07-13 |
ITRM20030247A1 (en) | 2004-11-21 |
AU2004240831B2 (en) | 2010-05-13 |
CA2526275A1 (en) | 2004-12-02 |
JP2007535904A (en) | 2007-12-13 |
AU2004240831A1 (en) | 2004-12-02 |
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