WO1999015651A1 - Polypeptides synthetiques pour le diagnostic et le traitement de maladies a prion - Google Patents

Polypeptides synthetiques pour le diagnostic et le traitement de maladies a prion Download PDF

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Publication number
WO1999015651A1
WO1999015651A1 PCT/EP1998/005924 EP9805924W WO9915651A1 WO 1999015651 A1 WO1999015651 A1 WO 1999015651A1 EP 9805924 W EP9805924 W EP 9805924W WO 9915651 A1 WO9915651 A1 WO 9915651A1
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WO
WIPO (PCT)
Prior art keywords
tyr
gly
asn
sequences
val
Prior art date
Application number
PCT/EP1998/005924
Other languages
German (de)
English (en)
Inventor
Markus Moser
Bruno Oesch
Carsten Korth
Original Assignee
Prionics Ag
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 Prionics Ag filed Critical Prionics Ag
Priority to EP98951427A priority Critical patent/EP1012287A1/fr
Priority to AU97448/98A priority patent/AU9744898A/en
Publication of WO1999015651A1 publication Critical patent/WO1999015651A1/fr

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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

  • Synthetic polypeptides for the diagnosis and therapy of prion diseases are synthetic polypeptides for the diagnosis and therapy of prion diseases.
  • the present invention relates to synthetic polypeptides which can be used in particular in the diagnosis, prevention and treatment of a number of communicable, degenerative neurological diseases. These diseases are summarized under the term spongiform encephalopathies or prion diseases. They occur in different mammalian species, e.g. as scrapie in sheep, as BSE in cows and as Kuru or Creutzfeldt-Jakob disease in humans.
  • PrpSc disease-specific prion protein
  • p r pSc un jp r pC
  • PrPC for example, predominantly has ⁇ -helical secondary structures, is soluble and protease-digestible
  • Pi-pSc has mainly ß-sheet structures, is insoluble and is only partially degraded by proteases.
  • PiPSc.pioteine is believed to be able to convert normal PrPC proteins to disease specific folding, which would explain the infectivity of P pSc pireins.
  • the object of the invention is to provide synthetic polypeptides which have immunogenic properties or generally binding properties of the Pi-pSc but not its infectivity.
  • PrP denotes the prion protein generally regardless of its conformation
  • PrPSc-binding substances in, for example, the mapping experiments described below.
  • PrP denotes the prion protein generally regardless of its conformation
  • PrPSc-binding substances There are a number of different PrpSc_ S p e zif ⁇ sch binding substances. Examples of this are given below.
  • the synthetic polypeptides according to the invention thus contain at least one sequence which is present on the surface of the native Pi-pSc. is arranged and form a binding site there alone or in conjunction with further of the sequences that can be used in the context of the invention.
  • At least one or both of the ⁇ -sheet structures present in the structural model of the recombinant PrP are involved in the formation of these PrPSc-specific surface structures. It is assumed that these structures have a dominant influence in the PrpSc as a nucleation point in the formation of the surface.
  • the invention in particular includes synthetic polypeptides which have one or more of the following sequence regions mentioned in claim 2:
  • R ⁇ Asn or Ser
  • R 2 Tip or Tyr
  • R3 Arg or Lys
  • R4 Met
  • R5 Gin, Glu or Arg
  • R Ser or Asn
  • R7 Val, Thr or Ile
  • Rg Gin or Glu
  • Ro, Lys, Arg or Gin
  • Rio Gin or Glu
  • R 1 ⁇ Tyr, Ser or Ala
  • Rj2 His, Tyr or Asn and the amino acids specified in Klaimnem are not mandatory are.
  • further synthetic polypeptides within the scope of the invention can contain one or more of the following sequences: e) Gly-Tip-Gly-Gln-Pro-His-Gly-Gly-Gly-Tip-Gly-Gln-Pro-His-Gly f) Lys-Pro-R ⁇ -Lys-Pro-Lys-Thi-R ⁇ -R ⁇ -Lys-His-Rie-Ala-Gly g) Tyr-Ri g-Leu-Gly-Ser h) Ser-Ala-Met-Ser-A ⁇ g-Pro-Ri7-Ri7-His-Phe-Gly-Ri4 -Asp i) Asn-Met-R 18 -A ⁇ g-Tyr- (PiO-Ri4) - (Gln-Val-Tyr-Tyr-R 19 )
  • rbPrP a cell line (for example E.
  • coli with a vector expressing rbPrP is grown in a suitable medium (for example Luria-Broth) and the prion protein is then extracted from the cells' inclusion bodies after lysis and other conventional cleaning methods are isolated (see also Homemann et al., FEBS-Letters (97) 413 (2; 277-281)).
  • a suitable medium for example Luria-Broth
  • prion protein is then extracted from the cells' inclusion bodies after lysis and other conventional cleaning methods are isolated (see also Homemann et al., FEBS-Letters (97) 413 (2; 277-281)).
  • 15B3 is a monoclonal PrP ⁇ c antibody recently discovered by the inventors. Hybridoma cells that produce the above-mentioned (PrPSc-specific) antibodies 15B3 were deposited on February 13, 1997 under the Nuimner DSM ACC2298 at the German Collection of Microorganisms and Cell Cultures GmbH in Braunschweig.
  • the two different binding substances the antibody 15B3 and the recombinant rbPrP, recognized the sequences a-d according to claim 1, as shown for 15B3 in FIG. 1 and for rbPrP in FIG. 2.
  • FIGS. 1 and 2 denote the different peptide sequences of the bank to which the monoclonal antibody 15B3 or rbPrP binds.
  • the sequences according to the invention each correspond to the regions common to the respective spatially adjacent binding peptides.
  • FIG. 2 shows the result of a mapping experiment, the conditions of which correspond to the experiment shown in FIG. 1.
  • the antibody 15B3 was exchanged for recombinant bovine rbPrP.
  • the binding sites of the recombinant rbPrP are included in the representation, which for technical reasons cannot be better reproduced Highlights highlighted.
  • the binding sites are the same as in FIG. 1.
  • FIG. 3 shows the corresponding peptide bank with the colored binding regions, from which the sequences e-i were determined as indicated above.
  • sequences a-d and e-i are non-linearly connected sequences from PrP.
  • the claimed sequences thus represent sequence regions which are recognized individually in a peptide bank by, for example, a PrP ⁇ c -specific antibody and which, moreover, are highly likely to form a superficial binding region, for example an epitope, individually or in groups in the native Pi-pSc protein. Under epitope, the specific antigenic site on the
  • the synthetic polypeptides can be minimally derived from only one of the e.g. in claim 2 or said sequences. However, it is also possible to combine them with suitable further sequences, which are referred to below as conformation sequences.
  • a polypeptide in this embodiment can have one of the following two sequences:
  • sequence j contains in its C-terminal region the sequence b, which is e.g. the spacer Gly-Gly is connected to the N-terminal adjoining conformational sequence.
  • sequence k the sequence is exactly the opposite.
  • Other suitable spacers are generally all those sequences which guarantee sufficient flexibility between the linked peptide regions and have no influence on the conformation.
  • amino acids contained in peptide sequences can be replaced by corresponding acids from the same group without the properties of the sequence being changed thereby.
  • the invention therefore also includes those sequences which do not correspond to the formulas mentioned explicitly, but in which one or more amino acids have been replaced by a homologous acid.
  • amino acid sequences regardless of their direction of formation, may have similar binding properties, in particular antibody binding properties, under certain circumstances.
  • retro-amino acid sequences refers to corresponding sequences that are formed in the C- or N-terminal direction (eg [N-te ⁇ ninal] -Glu-Ala-Val-Leu- [C-terminal], [N - terminal] -Leu-Val-Ala-Glu- [C-te ⁇ ninal]).
  • the amino acids used are present in the chiral D counterform instead of the L forms found in animals, the epitope regions are formed in mirror image and are also identified by some antibodies, the isotypes of the antibodies differing in these properties.
  • retro-inverse amino acid sequences are that D-amino acids are broken down more slowly by the organism, since they are poorly recognized by the degrading enzymes. The same effect can also be achieved by substituting non-natural amino acids.
  • the peplides according to the invention can therefore also be present in retro- and / or inverse form or, furthermore, also contain non-natural (ie not produced by the organism) amino acids.
  • Non-natural amino acids can be produced by synthesizing, for example, additional side chains or reactive groups with specific properties and adapted to specific applications.
  • the synthetic polypeptides according to the invention can be used in particular in the treatment, prevention or diagnosis of prion diseases.
  • the synthetic polypeptides according to the invention is particularly contemplated to present the synthetic polypeptides according to the invention as a vaccine.
  • a sufficient amount of peptide is dissolved with Freund's complete adjuvant and injected subcutaneously or intramuscularly.
  • an immunogenic amount of peptide is again dissolved in Freund's incomplete adjuvant and injected (boost).
  • the goal of vaccination is to provoke an immune response that is endogenous to production of antibodies, which specifically recognize and neutralize or label PrpSc, so that the body's own defense mechanisms can prevent a disease or slow down or stop the disease process.
  • binding properties can be seen e.g. take advantage of the therapy. It would be conceivable to apply the polypeptides according to the invention to the body of a sick patient and to infectious ones there
  • Pi-pSc available as a binding partner. This could potentially drastically reduce the conversion rate and slow the progression of the disease.
  • the synthetic polypeptides according to the invention are not restricted to the specified sequences.
  • Peptides that are in a derivatized form are also conceivable.
  • a camer or immunogen such as diphtheria oxide or BSA
  • Another possibility of derivatization would be the linkage with markers such as biotin or peroxidase or with enzymes or nucleic acids.
  • pre-signal sequences hen which facilitate the patency of the peptides into the desired compartments.
  • the Blood-Him-Scluanke is being considered, the passage of which could be facilitated by using signal sequences which bind, for example, to the transferrin receptor.
  • the synthetic polypeptides according to the invention are to be used in the therapy, diagnosis and prophylaxis of prion diseases.
  • polypeptides can be prepared in any manner. Either directly using conventional peptide synthesis techniques or indirectly using RNA or DNA synthesis and then using conventional molecular biological techniques. Accordingly, a further aspect of the invention is directed to a DNA molecule which is able to code one of the polypeptides according to the invention. Such a DNA molecule (preferably also in a longer sequence) is preferably made available in a suitable expression vector. These are routine techniques.
  • the invention also relates to a kit for diagnosing PrPSc or antibodies to PrP ⁇ c . which contains at least one of the polypeptides according to the invention.
  • a kit for diagnosing PrPSc or antibodies to PrP ⁇ c which contains at least one of the polypeptides according to the invention.
  • This takes advantage of the fact that the polypeptides are able to bind specifically to the Pi-pSc and to the antibodies directed against it.
  • one of the binding substances used to cut the polypeptide sequences can be recombinant bovine rbPrP. It has surprisingly been found that recombinant rbPrP is able to bind specifically to PrpSc Z u and to recognize the same sequences as the antibody 15B3 on the corresponding peptide bank (see FIG. 2).
  • a further aspect of the invention therefore relates to the use of recombinant rbPrP protein corresponding to the sequence in FIG. 4. It has been found that when recombinant rbPrP is administered, PrPSc-specific antibodies are produced with the specified sequence. This effect can be exploited particularly in the context of prophylaxis or therapy by giving a patient recombinant rbPrP prepared as a vaccine and triggering a corresponding immune response.
  • the configuration is of course not limited to the use of bovine rbPrP according to FIG. 4.
  • Recombinant PrP sequences with species-specific deviations from the rbPrP sequence shown in FIG. 4 may equally well be used.
  • the invention also relates to a method for producing
  • PrPSc-specific antibodies For immunization, at least one of the polypeptides according to the invention is administered to non-human mammals in a dose sufficient for immunization and the antibody formed against it is isolated using customary methods.
  • peptides according to the invention are also suitable for use in so-called pharmaceutical or chemical libraries with which new ones are used
  • MOLECULE TYPE Protein
  • HYPOTHETICAL YES
  • ANTISENSE NO

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Zoology (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Toxicology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention concerne un polypeptide synthétique contenant une ou plusieurs séquences définies de PrP ou bien des séquences dérivées de ceux-ci, qui sont reconnnues par des substances fixant les PrPSc.
PCT/EP1998/005924 1997-09-20 1998-09-17 Polypeptides synthetiques pour le diagnostic et le traitement de maladies a prion WO1999015651A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP98951427A EP1012287A1 (fr) 1997-09-20 1998-09-17 Polypeptides synthetiques pour le diagnostic et le traitement de maladies a prion
AU97448/98A AU9744898A (en) 1997-09-20 1998-09-17 Synthetic polypeptide for diagnosing and treating prion-related diseases

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19741607A DE19741607A1 (de) 1997-09-20 1997-09-20 Synthetische Polypeptide zur Diagnose und Therapie von Prionerkrankungen
DE19741607.1 1997-09-20

Publications (1)

Publication Number Publication Date
WO1999015651A1 true WO1999015651A1 (fr) 1999-04-01

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EP (1) EP1012287A1 (fr)
AU (1) AU9744898A (fr)
DE (1) DE19741607A1 (fr)
WO (1) WO1999015651A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001077687A2 (fr) * 2000-04-05 2001-10-18 V.I Technologies, Inc. Ligands de fixation au prion et procedes d'utilisation correspondants
WO2004018511A2 (fr) * 2002-08-23 2004-03-04 Copenhagen Biotech Assets Aps Composes peptidiques composites destines au diagnostic et au traitement de maladies induites par des proteines prions
EP1572937A2 (fr) * 2002-04-09 2005-09-14 The Scripps Research Institute Polypeptides hybrides a greffe de motif structural et utilisations de ceux-ci
DE102004043782A1 (de) * 2004-09-08 2006-03-09 Heinrich-Heine-Universität Düsseldorf Polypeptide und Verfahren zur spezifischen Bindung von Prionen
US7041807B1 (en) 1999-06-23 2006-05-09 Caprion Pharmaceuticals, Inc. Antibodies to a YYX epitope of a mammalian prion protein
US7435540B2 (en) 2002-09-27 2008-10-14 Idexx Corporation PrPSc-selective peptides
US7439041B2 (en) 2003-08-13 2008-10-21 Novartis Vaccines And Diagnostics, Inc. Prion-specific peptide reagents
US7834144B2 (en) 2005-09-09 2010-11-16 Novartis Ag Prion-specific peptoid reagents
US8030484B2 (en) 2004-07-27 2011-10-04 Prometic Biosciences Limited Substituted triazines as prion protein ligands and their use to detect or remove prions
US8501939B2 (en) 2005-06-10 2013-08-06 Prometic Biosciences Limited Triazines and pyrimidines as protein binding ligands

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6261790B1 (en) * 1999-07-15 2001-07-17 The United States Of America As Represented By The Secretary Of Agriculture Monoclonal antibodies and antibody cocktail for detection of prion protein as an indication of transmissible spongiform encephalopathies
DK1158003T4 (da) * 2000-05-23 2013-04-08 Blood Transfusion Ct Of Slovenia Antistoffer, som er i stand til selektivt at detektere prion PrP Sc-isoformer
US7098317B1 (en) 2000-05-23 2006-08-29 Blood Transfusion Center Of Slovenia Antibodies capable to selectively detect prion PrPSc isoforms
US20040053839A1 (en) * 2000-12-21 2004-03-18 Andrea Leblanc Method of protecting cells against apoptosis and assays to identify agents which modulate apoptosis
DE10108099A1 (de) * 2001-02-19 2002-09-12 Cenas Ag Verfahren zum Nachweis spezifischer Proteine und Verwendung
RU2267496C2 (ru) * 2004-01-15 2006-01-10 Сергей Иванович Черныш Противоопухолевые и антивирусные пептиды
WO2006076497A2 (fr) * 2005-01-13 2006-07-20 Novartis Vaccines And Diagnostics Inc. Isolation de prions pathogeniques
EA009555B1 (ru) * 2005-11-30 2008-02-28 Сергей Иванович Черныш Пептид, обладающий иммуномодулирующей активностью, и фармацевтическая композиция

Citations (5)

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Publication number Priority date Publication date Assignee Title
WO1993011155A1 (fr) * 1991-12-03 1993-06-10 Proteus Molecular Design Limited Fragments de proteines de prion
WO1993023432A1 (fr) * 1992-05-15 1993-11-25 New York University Polypeptides de pion solubles et procedes de detection et de purification
WO1997016728A1 (fr) * 1995-11-02 1997-05-09 The Regents Of The University Of California FORMATION ET UTILISATION DE COMPLEXES DE PROTEINES PRIONS (PrP)
WO1998035236A2 (fr) * 1997-02-06 1998-08-13 Enfer Technology Limited Dosage immunologique destine aux encephalopathies spongiformes
EP0861900A1 (fr) * 1997-02-21 1998-09-02 Erziehungsdirektion Of The Canton Zurich Détection immunologique de prions

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993011155A1 (fr) * 1991-12-03 1993-06-10 Proteus Molecular Design Limited Fragments de proteines de prion
WO1993023432A1 (fr) * 1992-05-15 1993-11-25 New York University Polypeptides de pion solubles et procedes de detection et de purification
WO1997016728A1 (fr) * 1995-11-02 1997-05-09 The Regents Of The University Of California FORMATION ET UTILISATION DE COMPLEXES DE PROTEINES PRIONS (PrP)
WO1998035236A2 (fr) * 1997-02-06 1998-08-13 Enfer Technology Limited Dosage immunologique destine aux encephalopathies spongiformes
EP0861900A1 (fr) * 1997-02-21 1998-09-02 Erziehungsdirektion Of The Canton Zurich Détection immunologique de prions

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KORTH, C. ET AL: "Prion (PrPSc)-specific epitope defined by a monoclonal antibody", NATURE (LONDON) (1997), 390(6655), 74-77 CODEN: NATUAS;ISSN: 0028-0836, 6 November 1997 (1997-11-06), XP002092791 *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7041807B1 (en) 1999-06-23 2006-05-09 Caprion Pharmaceuticals, Inc. Antibodies to a YYX epitope of a mammalian prion protein
WO2001077687A3 (fr) * 2000-04-05 2002-05-23 Vi Technologies Inc Ligands de fixation au prion et procedes d'utilisation correspondants
WO2001077687A2 (fr) * 2000-04-05 2001-10-18 V.I Technologies, Inc. Ligands de fixation au prion et procedes d'utilisation correspondants
US7939641B2 (en) 2002-04-09 2011-05-10 The Scripps Research Institute Motif-grafted hybrid polypeptides and uses thereof
EP1572937A2 (fr) * 2002-04-09 2005-09-14 The Scripps Research Institute Polypeptides hybrides a greffe de motif structural et utilisations de ceux-ci
EP1572937A4 (fr) * 2002-04-09 2007-08-08 Scripps Research Inst Polypeptides hybrides a greffe de motif structural et utilisations de ceux-ci
JP2009142285A (ja) * 2002-04-09 2009-07-02 Scripps Res Inst:The モチーフ・グラフトされたハイブリッドポリペプチドおよびその使用
EP2301959A3 (fr) * 2002-04-09 2013-03-13 The Scripps Research Institute Polypeptides hybrides à motifs greffés et leurs utilisations
WO2004018511A3 (fr) * 2002-08-23 2004-03-25 Copenhagen Biotech Assets Aps Composes peptidiques composites destines au diagnostic et au traitement de maladies induites par des proteines prions
WO2004018511A2 (fr) * 2002-08-23 2004-03-04 Copenhagen Biotech Assets Aps Composes peptidiques composites destines au diagnostic et au traitement de maladies induites par des proteines prions
US7435540B2 (en) 2002-09-27 2008-10-14 Idexx Corporation PrPSc-selective peptides
US7439041B2 (en) 2003-08-13 2008-10-21 Novartis Vaccines And Diagnostics, Inc. Prion-specific peptide reagents
US8030484B2 (en) 2004-07-27 2011-10-04 Prometic Biosciences Limited Substituted triazines as prion protein ligands and their use to detect or remove prions
DE102004043782A1 (de) * 2004-09-08 2006-03-09 Heinrich-Heine-Universität Düsseldorf Polypeptide und Verfahren zur spezifischen Bindung von Prionen
US8501939B2 (en) 2005-06-10 2013-08-06 Prometic Biosciences Limited Triazines and pyrimidines as protein binding ligands
US7834144B2 (en) 2005-09-09 2010-11-16 Novartis Ag Prion-specific peptoid reagents

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Publication number Publication date
DE19741607A1 (de) 1999-03-25
AU9744898A (en) 1999-04-12
EP1012287A1 (fr) 2000-06-28

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