WO2003025181A2 - Dna sequences that encode variable regions of antibodies that bind to the prion protein (prp), and prp-binding polypeptides - Google Patents
Dna sequences that encode variable regions of antibodies that bind to the prion protein (prp), and prp-binding polypeptides Download PDFInfo
- Publication number
- WO2003025181A2 WO2003025181A2 PCT/EP2002/009370 EP0209370W WO03025181A2 WO 2003025181 A2 WO2003025181 A2 WO 2003025181A2 EP 0209370 W EP0209370 W EP 0209370W WO 03025181 A2 WO03025181 A2 WO 03025181A2
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- Prior art keywords
- prp
- antibodies
- bind
- polypeptides
- variable regions
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
Definitions
- the invention relates to DNA sequences which each code for variable regions of two different antibodies binding to PrP.
- the invention relates to polypeptides which have PrP-binding peptide regions produced from the DNA sequences.
- Antibodies against PrP are specific and continue to allow diagnostic and preventive use.
- the object of the invention is to facilitate the production and optimization of polypeptides that bind to PrP. This is possible with the following DNA sequences according to the invention according to claim 1:
- gaggtccagc tgcaacagtc tggacctgag ctggtgaagc ctggggcttc agtgaagata ccctgcaagg cttctggata cacattcact gactacaaca tggactgggt gaagcagagc catggaaaga gccttgagtg gattggagat attaatccta acaatggtgg tactatctac aaccagaagt tcaagggcaa ggccacattg actgtagaca agtcctccag cacagcctac atggagctcc gcagcctgac atctgaggac actgcagtct attactgtgc aagggggc actgcagtct attactgtgc aagggggc actgcagt
- the DNA sequences according to the invention were determined on the basis of two antibodies described in WO 98/37210 and designated there with 6H4 and 15B3, which bind to different epitopes on the prion protein specified in WO 98/37210.
- Antibody 6H4 in particular could open up interesting therapeutic possibilities because it binds at the interface between prion protein dimers (Knaus et al., Nature Structural Biology, Volume 8, page 770; 2001) and dissolve a prion infection in a cell culture experiment (Enari et al, PNAS vol 98 , Pages 9295; 2001), and can prevent infection in the mouse experiment (Heppner et. Al, Science Vol 239, No. 5536 (in press)).
- sequences were obtained from 6H4 and 15B3 hybridoma cells as described by Heppner et. al. in Science Vol 239, No. 5536 (in press).
- sequences SEQ1 and SEQ2 according to the invention each code for variable regions of the heavy or light chain of the antibody 6H4.
- SEQ3 and SEQ4 each code for variable regions of the heavy and light chain of the 15B3 antibody.
- Antibodies are immunoglobulins that are made up of two protein chains called heavy and light chains. Both chains have identical conserved sequence segments for most antibodies. In addition, there are variable N-terminals on the heavy and light chains. contain rich with a length of about 110 amino acids, which are responsible for the specific binding of the respective antibody to a particular antigen.
- polypeptides which bind PrP or have at least one PrP-binding partial region can be produced in a simple manner.
- polypeptides according to the invention have the advantage over the antibodies available hitherto that their design can be tailored to a specific purpose.
- immunological properties of different antibodies can of course also be combined in a polypeptide according to the invention and then tested accordingly in therapeutic or diagnostic applications.
- humanization is of particular interest, as a result of which an antibody is produced which does not cause a defense reaction in the human body.
- DNA sequences according to the invention For humanization only one or more of the DNA sequences according to the invention have to be inserted instead of the variable region of a human antibody and the new antibody has to be produced using conventional methods.
- Also interesting and easy to implement with the invention are possible modifications of the binding property of the polypeptides by, for example, exchange modifications of individual amino acids and entire regions or also the combination of different DNA sequences or sequence regions according to the invention.
- polypeptides according to the invention cover a wide range, which ranges from modifications of the known antibodies to peptide fragments which comprise only one peptide sequence derived from one or more of the DNA sequences.
- polypeptides produced according to the invention can be used in the diagnosis, prevention and therapy of prion diseases.
Abstract
The invention relates to a DNA sequence that encodes variable regions of antibodies that bind to PrP. Said DNA sequence contains at least one sequence indicated under SEQ1 to SEQ4 or at least a part of said sequence, and encodes polypeptides that bind PrP. The invention further relates to a polypeptide derived from the DNA sequence, which comprises at least one PrP-binding region, except for the polypeptides that are identical to a chain of the antibodies 6H4 or 15B3, and to the use of the polypeptides in the therapy, diagnosis and prevention of prion-related diseases.
Description
DNA-Sequenzen codierend für variable Bereiche von Antikörpern, die an das Prion-Protein (PrP) binden, sowie PrP-bindende Polypeptide DNA sequences coding for variable regions of antibodies that bind to the prion protein (PrP) and PrP-binding polypeptides
Die Erfindung betrifft DNA-Sequenzen, die jeweils für variable Bereiche zweier unterschiedlicher an PrP bindende Antikörper codieren.The invention relates to DNA sequences which each code for variable regions of two different antibodies binding to PrP.
Weiterhin betrifft die Erfindung Polypeptide, die ausgehend von den DNA- Sequenzen hergestellte PrP-bindende Peptidbereiche aufweisen.Furthermore, the invention relates to polypeptides which have PrP-binding peptide regions produced from the DNA sequences.
Für die Behandlung von Prionenerkrankungenn werden unterschiedliche Substanzen vorgeschlagen, wie z.B. Congo-Rot, Amphothericin, Pentosan Sulfat oder auch ß-sheet brechende Peptide. Alle genannten Substanzen sind relativ unspezifisch und haben bislang den klinischen Verlauf höchstens verlangsamen nicht aber aufhalten können.Different substances are proposed for the treatment of prion diseases, e.g. Congo red, amphothericin, pentosan sulfate or ß-sheet breaking peptides. All of the substances mentioned are relatively unspecific and have so far not been able to slow the clinical course, but at least not to stop it.
Antikörper gegen PrP sind dagegen spezifisch und erlauben weiterhin auch einen diagnostischen und präventiven Einsatz.Antibodies against PrP, on the other hand, are specific and continue to allow diagnostic and preventive use.
Eine Optimierung herkömmlicher Antikörper für bestimmte Zwecke ist allerdings relativ schwierig.However, optimizing conventional antibodies for certain purposes is relatively difficult.
Aufgabe der Erfindung ist, die Herstellung und Optimierung von Polypeptiden, die an PrP binden, zu erleichtem.
Dies ist möglich mit den folgenden erfindungsgemäßen DNA Sequenzen nach Anspruch 1 :The object of the invention is to facilitate the production and optimization of polypeptides that bind to PrP. This is possible with the following DNA sequences according to the invention according to claim 1:
SEQl: . caggttcagg tgcagcagtc tggagctgag ctggcgaggc ctggggcttc agtgaagctg tcctgcaagg cttctgtcta cacctccgca agctatggta taagctgggt gaagcagaga actggacagg gccttgagtg gattggagag atttatccta gaagtggtaa tacttactac aatgagaagt tcaagggcaa ggccacactg actgcagaca aatcctccag cacagcgtac atggagctcc gcagcctgac atctgaggac tctgcggtct atttctgtgc aaatggttac ctgtttgctt actggggcca agggactctg 330SEQl:. caggttcagg tgcagcagtc tggagctgag ctggcgaggc ctggggcttc agtgaagctg tcctgcaagg cttctgtcta cacctccgca agctatggta taagctgggt gaagcagaga actggacagg gccttgagtg gattggagag atttatccta gaagtggtaa tacttactac aatgagaagt tcaagggcaa ggccacactg actgcagaca aatcctccag cacagcgtac atggagctcc gcagcctgac atctgaggac tctgcggtct atttctgtgc aaatggttac ctgtttgctt actggggcca agggactctg 330
SEQ2: gacatccaga tgacccagtc tccatcctcc ttatctgcct ctctgggaga aagagtcagt ctcacttgtc gggcaagtca ggacattggt ggtagcttaa actggcttca gcaggaacca gatggcacta ttaaacgcct gatctacgcc acatccagtt tagattctgg tgtccccaaa aggttcagtg gcagtaggtc tgggtcagat tattctctca ccatcagcag ccttgagtct gaagattttg tagactatta ctgtctacaa tatgctagtt ctccgtacac gttcggaggg gggaccaagc tggaaataaa acgt 324SEQ 2: gacatccaga tgacccagtc tccatcctcc ttatctgcct ctctgggaga aagagtcagt ctcacttgtc gggcaagtca ggacattggt ggtagcttaa actggcttca gcaggaacca gatggcacta ttaaacgcct gatctacgcc acatccagtt tagattctgg tgtccccaaa aggttcagtg gcagtaggtc tgggtcagat tattctctca ccatcagcag ccttgagtct gaagattttg tagactatta ctgtctacaa tatgctagtt ctccgtacac gttcggaggg gggaccaagc tggaaataaa ACGT 324
SEQ3: gaggtccagc tgcaacagtc tggacctgag ctggtgaagc ctggggcttc agtgaagata ccctgcaagg cttctggata cacattcact gactacaaca tggactgggt gaagcagagc catggaaaga gccttgagtg gattggagat attaatccta acaatggtgg tactatctac aaccagaagt tcaagggcaa ggccacattg actgtagaca agtcctccag cacagcctac atggagctcc gcagcctgac atctgaggac actgcagtct attactgtgc aagggggggc gtatggttac gacggacgtc cccgtttgct 330SEQ3: gaggtccagc tgcaacagtc tggacctgag ctggtgaagc ctggggcttc agtgaagata ccctgcaagg cttctggata cacattcact gactacaaca tggactgggt gaagcagagc catggaaaga gccttgagtg gattggagat attaatccta acaatggtgg tactatctac aaccagaagt tcaagggcaa ggccacattg actgtagaca agtcctccag cacagcctac atggagctcc gcagcctgac atctgaggac actgcagtct attactgtgc aagggggggc gtatggttac gacggacgtc cccgtttgct 330
SEQ4: agaggacaaa ttgttctcac ccagtctcca gcaatcatgt ctgcatctcc aggggagaag gtcaccatga cctgcagtgc cagctcaagt gtaagttaca tgcactggta ccagcagaag tcaggcacct cccccaaaag atggatttat gacacatcca aactggcttc tggagtccct gctcgcttca gtggcagtgg gtctgggacc tcttactctc tcacaatcag cagcatggag gctgaagatg ctgccactta ttactgccag cagtggagta gtaacccacc cacgttcgga ggggggacca agctggaaat aaaa 324
Die Erfindung ist nicht auf die in SEQl - SEQ4 angegebenen DNA-Sequenzen beschränkt sondern umfaßt auch damit homologe bzw. abgewandelte Sequenzen, solange auf Basis dieser Sequenzen Peptide bzw. Peptidabschnitte herstellbar sind, die an PrP binden.SEQ4: agaggacaaa ttgttctcac ccagtctcca gcaatcatgt ctgcatctcc aggggagaag gtcaccatga cctgcagtgc cagctcaagt gtaagttaca tgcactggta ccagcagaag tcaggcacct cccccaaaag atggatttat gacacatcca aactggcttc tggagtccct gctcgcttca gtggcagtgg gtctgggacc tcttactctc tcacaatcag cagcatggag gctgaagatg ctgccactta ttactgccag cagtggagta gtaacccacc cacgttcgga ggggggacca agctggaaat aaaa 324 The invention is not restricted to the DNA sequences specified in SEQ1-SEQ4, but also includes homologous or modified sequences, as long as peptides or peptide segments that bind to PrP can be produced on the basis of these sequences.
Die Ermittlung der erfindungsgemäßen DNA-Sequenzen erfolgte ausgehend von zwei in der WO 98/37210 beschriebenen und dort mit 6H4 und 15B3 bezeichneten Antikörpern, die an unterschiedliche, in der WO 98/37210 spezifizierte Epi- tope auf dem Prionprotein binden. Insbesondere der Antikörper 6H4 könnte interessante therapeutische Möglichkeiten eröffnen, da er an der Grenzfläche zwischen Prionproteindimeren bindet (Knaus et al., Nature Structural Biology, Volume 8, Seite 770; 2001) und im Zellkulturexperiment eine Prioneninfektion auflösen (Enari et al, PNAS vol 98, Seiten 9295; 2001), sowie im Maus- Experiment eine Infektion verhindern kann (Heppner et. al, Science Vol 239, Nr. 5536 (im Druck)).The DNA sequences according to the invention were determined on the basis of two antibodies described in WO 98/37210 and designated there with 6H4 and 15B3, which bind to different epitopes on the prion protein specified in WO 98/37210. Antibody 6H4 in particular could open up interesting therapeutic possibilities because it binds at the interface between prion protein dimers (Knaus et al., Nature Structural Biology, Volume 8, page 770; 2001) and dissolve a prion infection in a cell culture experiment (Enari et al, PNAS vol 98 , Pages 9295; 2001), and can prevent infection in the mouse experiment (Heppner et. Al, Science Vol 239, No. 5536 (in press)).
Die Sequenzen wurden aus 6H4 und 15B3 Hybridoma Zellen gewonnen, wie von Heppner et. al. in Science Vol 239, Nr. 5536 (im Druck) beschrieben.The sequences were obtained from 6H4 and 15B3 hybridoma cells as described by Heppner et. al. in Science Vol 239, No. 5536 (in press).
Die erfindungsgemäßen Sequenzen SEQl und SEQ2 codieren jeweils für variable Bereiche der Heavy- bzw- Light-Chain des Antikörpers 6H4.The sequences SEQ1 and SEQ2 according to the invention each code for variable regions of the heavy or light chain of the antibody 6H4.
SEQ3 und SEQ4 codieren jeweils für variable Bereiche der Heavy- bzw. Light- Chain des Antikörpers 15B3.SEQ3 and SEQ4 each code for variable regions of the heavy and light chain of the 15B3 antibody.
Antikörper sind Immunglobuline, die aus zwei Proteinketten aufgebaut sind, die als Heavy- bzw. Light-Chain bezeichnet werden. Beide Ketten weisen bei den meisten Antikörpern übereinstimmende konservierte Sequenzabschnitte auf. Daneben sind jeweils N-terminal auf der Heavy- und der Light-Chain variable Be-
reiche mit einer Länge von ca. 110 Aminosäuren enthalten, die für die spezifische Bindung des jeweiligen Antikörpers an ein bestimmtes Antigen verantwortlich sind.Antibodies are immunoglobulins that are made up of two protein chains called heavy and light chains. Both chains have identical conserved sequence segments for most antibodies. In addition, there are variable N-terminals on the heavy and light chains. contain rich with a length of about 110 amino acids, which are responsible for the specific binding of the respective antibody to a particular antigen.
Ausgehend von den erfindungsgemäßen DNA-Sequenzen lassen sich in einfacher Weise Polypeptide herstellen, die PrP binden bzw. mindestens einen PrP- bindenden Teilbereich aufweisen.Starting from the DNA sequences according to the invention, polypeptides which bind PrP or have at least one PrP-binding partial region can be produced in a simple manner.
Die erfϊndungsgemäßen Polypeptide haben dabei gegenüber den bislang zur Verfügung stehenden Antikörpern den Vorteil, daß ihr Design gezielt auf einen bestimmten Zweck abgestimmt werden kann.The polypeptides according to the invention have the advantage over the antibodies available hitherto that their design can be tailored to a specific purpose.
Denkbar ist z.B. die Herstellung von Polypeptiden, die neben den von den DNA- Sequenzen codierten Bereichen, weitere Bereiche mit speziellen Eigenschaften aufweisen.It is conceivable e.g. the production of polypeptides which, in addition to the regions encoded by the DNA sequences, have further regions with special properties.
Interessant ist in diesem Zusammenhang z.B. eine Optimierung im Hinblick auf die Überwindung der Blut-Hirn Schranke, die man mit der Erfindung mit vielen unterschiedlichen Konstrukten auf einfache Weise durchführen kann.It is interesting in this context e.g. an optimization with a view to overcoming the blood-brain barrier, which can be carried out in a simple manner with the invention using many different constructs.
Außerdem lassen sich in einem erfindungsgemäßen Polypeptid selbstverständlich auch immunologische Eigenschaften unterschiedlicher Antikörper verbinden und dann entsprechend in therapeutischen oder diagnostischen Anwendungen testen. In diesem Zusammenhang ist z.B. eine Humanisierung von besonderem Interesse, als deren Ergebnis ein Antikörper entsteht, der im menschlichen Körper keine Abwehrreaktion hervorruft. Zur Humanisierung müssen lediglich eine oder mehrere der erfindungsgemäßen DNA-Sequenzen anstelle der variablen Region eines humanen Antikörpers eingefügt werden und der neue Antikörper mit herkömmlichen Methoden hergestellt werden.
Weiterhin interessant und mit der Erfindung leicht umsetzbar sind mögliche Modifikationen der Bindungseigenschaft der Polypeptide durch z.B. Austauschmodifikationen einzelner Aminosäuren und ganzer Bereiche oder auch die Kombination unterschiedlicher erfindungsgemäßer DNA-Sequenzen oder Sequenzbereiche.In addition, immunological properties of different antibodies can of course also be combined in a polypeptide according to the invention and then tested accordingly in therapeutic or diagnostic applications. In this context, for example, humanization is of particular interest, as a result of which an antibody is produced which does not cause a defense reaction in the human body. For humanization only one or more of the DNA sequences according to the invention have to be inserted instead of the variable region of a human antibody and the new antibody has to be produced using conventional methods. Also interesting and easy to implement with the invention are possible modifications of the binding property of the polypeptides by, for example, exchange modifications of individual amino acids and entire regions or also the combination of different DNA sequences or sequence regions according to the invention.
Aus obigem ergibt sich, daß die erfindungsgemäßen Polypeptide eine große Bandbreite abdecken, die von Modifikationen der bekannten Antikörper bis hin zu Peptidfragmenten reicht, die nur eine von einer oder mehreren der DNA- Sequenzen abgeleitete Peptidsequenz umfassen.It follows from the above that the polypeptides according to the invention cover a wide range, which ranges from modifications of the known antibodies to peptide fragments which comprise only one peptide sequence derived from one or more of the DNA sequences.
Wie schon angesprochen, können die erfindungsgemäß hergestellten Polypeptide bei der Diagnose, der Prävention und der Therapie von Prionerkrankungen zum Einsatz kommen.
As already mentioned, the polypeptides produced according to the invention can be used in the diagnosis, prevention and therapy of prion diseases.
Claims
1. DNA-Sequenz codierend für variable Bereiche von Antikörpern, die an PrP binden, wobei die DNA-Sequenz mindestens eine der unter SEQl bis SEQ4 angegebenen Sequenzen oder mindestens einen Teilbereich dieser Sequenzen enthält und für Polypeptide codiert, die PrP binden.1. DNA sequence coding for variable regions of antibodies which bind to PrP, the DNA sequence containing at least one of the sequences given under SEQ1 to SEQ4 or at least a partial region of these sequences and coding for polypeptides which bind PrP.
2. Polypeptid mit mindestens einem Bereich, der PrP bindet, wobei der PrP- bindende Bereich aus einer der Sequenzen gemäß Anspruch 1 ableitbar ist, ausgenommen Polypeptide, die mit einer Kette der Antikörper 6H4 oder 15B3 identisch sind.2. Polypeptide with at least one region that binds PrP, the PrP-binding region being derivable from one of the sequences according to claim 1, with the exception of polypeptides which are identical to a chain of antibodies 6H4 or 15B3.
3. Verwendung der Polypeptide gemäß Anspruch 2 zur Therapie, Diagnose oder Prävention von Prionerkrankungen.
3. Use of the polypeptides according to claim 2 for the therapy, diagnosis or prevention of prion diseases.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP02772185A EP1423520A2 (en) | 2001-09-05 | 2002-08-22 | Dna sequences that encode variable regions of antibodies that bind to the prion protein (prp), and prp-binding polypeptides |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10143647.5 | 2001-09-05 | ||
| DE2001143647 DE10143647A1 (en) | 2001-09-05 | 2001-09-05 | New DNA sequences encoding antibody variable regions, useful for preparation of polypeptides for treatment, prevention and diagnosis of prion diseases |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2003025181A2 true WO2003025181A2 (en) | 2003-03-27 |
| WO2003025181A3 WO2003025181A3 (en) | 2003-09-25 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2002/009370 WO2003025181A2 (en) | 2001-09-05 | 2002-08-22 | Dna sequences that encode variable regions of antibodies that bind to the prion protein (prp), and prp-binding polypeptides |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP1423520A2 (en) |
| DE (1) | DE10143647A1 (en) |
| WO (1) | WO2003025181A2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004050120A2 (en) * | 2002-11-29 | 2004-06-17 | Medical Research Council | Treatment of prion-induced diseases by administration fo anti-prion antibodies |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998037210A1 (en) * | 1997-02-21 | 1998-08-27 | KANTON ZÜRICH vertreten durch DIE ERZIEHUNGSDIREKTION | Immunological detection of prions |
-
2001
- 2001-09-05 DE DE2001143647 patent/DE10143647A1/en not_active Withdrawn
-
2002
- 2002-08-22 WO PCT/EP2002/009370 patent/WO2003025181A2/en not_active Application Discontinuation
- 2002-08-22 EP EP02772185A patent/EP1423520A2/en not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998037210A1 (en) * | 1997-02-21 | 1998-08-27 | KANTON ZÜRICH vertreten durch DIE ERZIEHUNGSDIREKTION | Immunological detection of prions |
Non-Patent Citations (1)
| Title |
|---|
| HEPPNER F L ET AL: "PREVENTION OF SCRAPIE PATHOGENESIS BY TRANSGENIC EXPRESSION OF ANTI-PRION PROTEIN ANTIBODIES" SCIENCE, AMERICAN ASSOCIATION FOR THE ADVANCEMENT OF SCIENCE,, US, Bd. 294, 2001, Seiten 178-182, XP001094132 ISSN: 0036-8075 in der Anmeldung erw{hnt * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004050120A2 (en) * | 2002-11-29 | 2004-06-17 | Medical Research Council | Treatment of prion-induced diseases by administration fo anti-prion antibodies |
| WO2004050120A3 (en) * | 2002-11-29 | 2004-09-23 | Medical Res Council | Treatment of prion-induced diseases by administration fo anti-prion antibodies |
| US7550144B2 (en) | 2002-11-29 | 2009-06-23 | D-Gen Limited | Prion inhibition |
Also Published As
| Publication number | Publication date |
|---|---|
| DE10143647A1 (en) | 2003-03-27 |
| WO2003025181A3 (en) | 2003-09-25 |
| EP1423520A2 (en) | 2004-06-02 |
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