WO2002087304A2 - Peptides d'interleukine-2 et peptides et dimeres peptidiques derives d'interleukine-2 - Google Patents

Peptides d'interleukine-2 et peptides et dimeres peptidiques derives d'interleukine-2 Download PDF

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Publication number
WO2002087304A2
WO2002087304A2 PCT/EP2002/004679 EP0204679W WO02087304A2 WO 2002087304 A2 WO2002087304 A2 WO 2002087304A2 EP 0204679 W EP0204679 W EP 0204679W WO 02087304 A2 WO02087304 A2 WO 02087304A2
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WO
WIPO (PCT)
Prior art keywords
linker
aptssstkkt
qlqlehx
qmilnginn
flnrwit
Prior art date
Application number
PCT/EP2002/004679
Other languages
German (de)
English (en)
Inventor
Udo Haberl
Andreas Rybka
Christian Frosch
Raimund Wieser
Original Assignee
Frohnhofen, Wilfried
Tietmann, Andreas
Staudacher, Gerhard
Geyr, Florian
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 Frohnhofen, Wilfried, Tietmann, Andreas, Staudacher, Gerhard, Geyr, Florian filed Critical Frohnhofen, Wilfried
Publication of WO2002087304A2 publication Critical patent/WO2002087304A2/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
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/55—IL-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to IL2-related peptide monomers or peptide dimers, processes for their preparation, medicaments containing these peptide monomers or peptide dimers and their use in selected indications.
  • cytokines are endogenous messenger substances that are synthesized by different cells and then secreted.
  • the tasks of these cytokines are very diverse and z. Not fully understood yet, but mainly they have fundamental immunoregulatory effects.
  • Interleukin 2 is a cytokine used in tumor therapy. It is a protein consisting of 133 amino acids with a molecular weight of 15.4 kDa. IL2 binds to specific receptors, whereby the IL2-specific intracellular signals are triggered.
  • the high affinity receptor is a receptor complex consisting of the subunits D Q and 0 (each also referred to as p55, p75 and p64).
  • the intermediate affinity receptor complex consists of pp75 and p64, while the low affinity receptor has only p55.
  • IL2 has stimulating effects on the growth of T and B lymphocytes, activates cytotoxic and cytolytic NK cells and is therefore of central importance in regulating the immune response.
  • IL2 thus plays a fundamental role in the immune response against tumors and in inflammatory reactions.
  • One of the mechanisms that is important for IL2 tumor defense seems to be the induction of LAKs ("lymphokine activated killer” cells).
  • LAKs lymphokine activated killer cells.
  • Various attempts have been made in the past to treat tumor therapy with IL2.
  • the invention is essentially based on the technical problem of providing compounds with a biological activity of IL2 in such a way that the previous disadvantages of the prior art are avoided, i. H. that when administered as a pharmaceutical, fewer side effects, a longer half-life and high biological activity are obtained.
  • the solution to this technical problem has been achieved by the provision of the embodiment forms characterized in the patent claims.
  • the invention therefore relates to IL2-related peptide monomers or peptide dimers according to one of the general formulas
  • TIVX 6 FLNRWIT FX 7 QSX S ISTLT -Linker- APTSSSTKKT QLQLEHX 1 X 2 X 3 X 4 X 5 QMILNGINN (heterodimer 2), • APTSSSTKKT QLQLEHX 1 X 2 X 3 X 4 X 5 QMILNGINN linker- APTSSSTKKT QLQLEHX 01 X 02 X 03 X 04 X 05 QMILNGINN (homodimer 1) or
  • X 1 and X 01 are independently selected from I or L
  • X 2 and X 02 are independently selected from I or L
  • X 3 and X 03 are independently selected from V or L
  • X 4 and X 04 are independently selected are selected from E or D
  • X 5 and X 05 independently of one another are selected from L or F
  • X 6 and X 06 are selected independently of one another from E or D
  • X 7 and X 07 are selected independently of one another from A, G or C
  • X 8 and X 08 are independently selected from A or I and the "linker" is selected from amino acids or cyclopeptides.
  • IL2-related peptide monomer or peptide dimer according to the invention is selected from one of the general formulas
  • APTSSSTKKT QLQLEHX 1 X 2 X 3 X 4 X 5 QMILNGINN -Linker- TIVX 6 FLNRWIT FX 7 QSX 8 ISTLT (heterodimer 1) or • TIVX 6 FLNRWIT FX 7 QSX 8 ISTLT -Linker- APTSSSTKKT
  • the “linker” is selected from
  • the peptide monomers represent the minimal structures of the IL2 molecule that are required for the interaction with the subunits of the IL2 receptor complex. This ensures the highest specificity and high biological activity combined with the least side effects. Particularly due to the amino acid exchange of lysine to aspartic acid in position 20 from the amino terminus, the peptide no longer has VLS, which means that the neuropsychiatric side effects and organ dysfunction are absent. VLS is probably due to a particular amino acid combination around position 20 (seen from the N-terminus).
  • the invention relates to peptide monomers, homodimers and heterodimers from peptide monomers which have the amino acid sequence APTSSSTKKT QLQLEHLLLD LQMILNGINN (monomer 1), TIVEFLNRWIT FCQSIISTLT (monomer 2) or APTSSSTKKT QLQLEHLLLD LQMILNGINN -Linker- TIVEFLNRWIT FCQSIISTLT or variants thereof, whereby the peptide monomers or heterodimers bind to the interleukin 2 receptor and can possibly trigger a cellular signal.
  • the present invention also relates to medicaments containing these monomers or heterodimers, also in combination with interleukin 12 or interleukin 12 peptide homodimers or IL12 peptide heterodimers.
  • medicaments containing these monomers or heterodimers, also in combination with interleukin 12 or interleukin 12 peptide homodimers or IL12 peptide heterodimers.
  • One embodiment of the present invention relates to synthetic homodimers or heterodimers from peptide monomers which have the amino acid sequence (see above), where the homodimers or heterodimers bind to the IL2 receptor and can trigger a cellular signal.
  • These dimers according to the invention are based on the knowledge that, for a high biological effect, the peptides must be used in dimerized form in order to activate the IL2-receptor complex. No distinction is made between the activation of the low-affinity, intermediate-affinity and high-affinity receptor complex, since in each case there is stimulation of the NK cell or LAK cell activity, which is necessary for the intended therapeutic success.
  • Another object of the invention is a process for the preparation of an IL2-related peptide monomer or peptide dimer according to the invention, in which the process is carried out as a solid-phase synthesis process, in which the growing peptide is successively bonded to the solid phase and is extended with the corresponding amino acids, with dimerization possibly being extended followed.
  • the peptides according to the invention are usually synthesized by known solid-phase synthesis processes, for example as described in Example 1 below.
  • the biological activity (binding to the receptor, triggering a cellular signal and growth-stimulating effect of T cells) is examined by methods known to the person skilled in the art, for example according to Dusch A. et al., Eur. Cytokine Network 3 (1992) 97 -102; Pruett SB et al. Im Unol. Invest. 14 (1986) 541-548 or, for example, also according to the methods described in the examples below.
  • the peptides described above are homodimers or heterodimers in which the monomers are linked via their C-termini or N-termini or the N-terminus of one monomer is linked to the C-terminus of the other monomer ,
  • the invention further relates to medicaments containing at least one IL2-related peptide monomer or peptide dimer according to the invention and, if appropriate, suitable additives and / or auxiliaries or carriers and, if appropriate, at least one further active ingredient.
  • the medicament contains IL 12, a peptide monomer or peptide dimer derived from IL 12 or recombinant IL12 as a further active ingredient.
  • Another object of the invention is the use of an IL2-related peptide monomer or peptide dimer according to the invention for the manufacture of a medicament for the treatment of diseases of the immune system, for example inflammation and arthritic processes; Diseases associated with increased cell proliferation, for example cancer, for example forms of carcinomas, sarcomas, lymphomas and leukemias; or infectious processes.
  • diseases of the immune system for example inflammation and arthritic processes
  • Diseases associated with increased cell proliferation for example cancer, for example forms of carcinomas, sarcomas, lymphomas and leukemias
  • infectious processes for example cancer, for example forms of carcinomas, sarcomas, lymphomas and leukemias.
  • the IL2 peptide dimers are preferably used individually or in combination with other therapeutic agents such as IL12. It has been shown that the combination of IL2 with IL12 leads to synergistic effects in tumor therapy.
  • IL2 peptide dimers are administered together with synthetically produced IL12 peptide dimers (for example according to application DE 199 19 148) or else with recombinantly produced IL12. Due to their small size, they can be microencapsulated, which results in depot forms with different duration of action - depending on the pore size of the capsules.
  • the depot form can be applied locally, so that the highest concentration of the active ingredient is guaranteed over a long period of time at the desired location (e.g. cancer focus).
  • the present invention relates to the medicaments containing homodimers or heterodimers according to the invention or to their use for the treatment of diseases of the immune system (for example inflammation and arthritic processes), of diseases which are associated with increased cell proliferation, for example cancer and infectious processes.
  • diseases of the immune system for example inflammation and arthritic processes
  • diseases which are associated with increased cell proliferation for example cancer and infectious processes.
  • cancers include, for example various forms of Carcin 'omen, sarcomas, lymphomas and leukemias.
  • the medicament according to the invention is optionally in combination with a suitable pharmaceutical carrier.
  • suitable carriers and the formulation of such medicaments are known to the person skilled in the art.
  • Suitable carriers include, for example, buffered saline solutions, water, emulsions, for example oil / water emulsions, wetting agents, sterile solutions ecc.
  • the medicament according to the invention can be in the form of an injection solution, tablet, ointment, suspension, emulsion, a suppository, an aerosol ecc. available. It can also be administered in the form of depots (microcapsules, zinc salts, liposomes, etc.).
  • the mode of administration of the drug depends, among other things, on the form in which the active ingredient is present, and can be administered orally or parenterally.
  • the individual processes are known to the person skilled in the art.
  • the appropriate dosage is determined by the attending physician and depends on various factors, for example the age, gender, weight of the patient, the type and stage of the disease, the type of administration ecc.

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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)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne des monomères ou des dimères peptidiques dérivés d'interleukine-2 (IL-2), leur procédé de production, des médicaments renfermant ces monomères ou dimères peptidiques, ainsi que leur utilisation dans le cadre d'indications sélectionnées.
PCT/EP2002/004679 2001-04-30 2002-04-27 Peptides d'interleukine-2 et peptides et dimeres peptidiques derives d'interleukine-2 WO2002087304A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10121221.6 2001-04-30
DE10121221 2001-04-30

Publications (1)

Publication Number Publication Date
WO2002087304A2 true WO2002087304A2 (fr) 2002-11-07

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Family Applications (1)

Application Number Title Priority Date Filing Date
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004104023A2 (fr) * 2003-05-23 2004-12-02 Aplagen Gmbh Synthese de peptides
WO2005021592A2 (fr) * 2003-08-28 2005-03-10 Merck Patent Gmbh Augmentation de la demi-vie circulante de proteines de type interleukine 2
WO2006053508A1 (fr) * 2004-11-16 2006-05-26 Centro De Inmunolgía Molecular Formulations inmunotherapeutiques a capacite de neutralisation de l'interleukine-2
WO2013177187A3 (fr) * 2012-05-22 2014-01-16 Massachusetts Institute Of Technology Traitement de tumeur synergique avec du pk il-2 étendu et des agents thérapeutiques
WO2023131270A1 (fr) * 2022-01-07 2023-07-13 Cure Genetics, Co., Limited Nouveaux polypeptides d'interleukine-2

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EA008305B1 (ru) * 2003-05-23 2007-04-27 Аплаген Гмбх Синтез пептидов
EP1810977A3 (fr) * 2003-05-23 2009-05-20 AplaGen GmbH Phases solides renfermant des complexes de métal chélates pour la préparation de peptides
WO2004104023A3 (fr) * 2003-05-23 2005-06-02 Aplagen Gmbh Synthese de peptides
WO2004104023A2 (fr) * 2003-05-23 2004-12-02 Aplagen Gmbh Synthese de peptides
EP1810977A2 (fr) * 2003-05-23 2007-07-25 AplaGen GmbH Phases solides renfermant des complexes de métal chélates pour la préparation de peptides
WO2005021592A3 (fr) * 2003-08-28 2005-06-09 Merck Patent Gmbh Augmentation de la demi-vie circulante de proteines de type interleukine 2
WO2005021592A2 (fr) * 2003-08-28 2005-03-10 Merck Patent Gmbh Augmentation de la demi-vie circulante de proteines de type interleukine 2
WO2006053508A1 (fr) * 2004-11-16 2006-05-26 Centro De Inmunolgía Molecular Formulations inmunotherapeutiques a capacite de neutralisation de l'interleukine-2
EA012072B1 (ru) * 2004-11-16 2009-08-28 Сентро Де Инмунология Молекулар Иммунотерапевтические композиции для получения аутоантител, способных предотвращать связывание интерлейкина-2 со своим рецептором, и их использование в лечении рака
EP2112160A3 (fr) * 2004-11-16 2010-01-13 Centro de Inmunologia Molecular Formulations immunothérapeutiques pour générer des anticorps capables d'éviter la liaison d'interleukine-2 sur son récepteur Leur utilisation pour le traitement du cancer
CN101061136B (zh) * 2004-11-16 2012-12-05 分子免疫中心 具有白介素-2中和能力的免疫治疗制剂
WO2013177187A3 (fr) * 2012-05-22 2014-01-16 Massachusetts Institute Of Technology Traitement de tumeur synergique avec du pk il-2 étendu et des agents thérapeutiques
US9844582B2 (en) 2012-05-22 2017-12-19 Massachusetts Institute Of Technology Synergistic tumor treatment with extended-PK IL-2 and therapeutic agents
WO2023131270A1 (fr) * 2022-01-07 2023-07-13 Cure Genetics, Co., Limited Nouveaux polypeptides d'interleukine-2

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