WO2010124259A1 - Allostéramères pour récepteurs du tnf et utilisations afférentes - Google Patents

Allostéramères pour récepteurs du tnf et utilisations afférentes Download PDF

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Publication number
WO2010124259A1
WO2010124259A1 PCT/US2010/032310 US2010032310W WO2010124259A1 WO 2010124259 A1 WO2010124259 A1 WO 2010124259A1 US 2010032310 W US2010032310 W US 2010032310W WO 2010124259 A1 WO2010124259 A1 WO 2010124259A1
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WO
WIPO (PCT)
Prior art keywords
peptide
seq
amino acids
peptides
receptor
Prior art date
Application number
PCT/US2010/032310
Other languages
English (en)
Inventor
Christiane Quiniou
Sylvain Chemtob
Shawn Barney
Original Assignee
Centre Hospitalier Universitaire Sainte-Justine
Allostera Pharma Inc.
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 Centre Hospitalier Universitaire Sainte-Justine, Allostera Pharma Inc. filed Critical Centre Hospitalier Universitaire Sainte-Justine
Publication of WO2010124259A1 publication Critical patent/WO2010124259A1/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
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • C07K14/7151—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for tumor necrosis factor [TNF], for lymphotoxin [LT]
    • 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 provides a peptide that is up to 25 amino acids long and has a sequence identical to at least 5 (e.g., at least 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, or 25) contiguous amino acids that appear in an extracellular or transmembrane region of a TNF receptor. In some embodiments, the present invention provides a peptide that is up to 25 amino acids long and has a sequence identical to at least 5 (e.g., at least 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, or 25) contiguous amino acids that appear in an extracellular or transmembrane region of a TNF receptor but in the inverse configuration.
  • the plurality of peptides has adjacent or overlapping sequences spanning the target or a portion thereof. In some embodiments, the plurality of peptides has overlapping sequences and wherein adjacent overlapping sequences shift by a pre-determined number of amino acids. In some embodiments, the pre-determined number is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids.
  • FIG. 2C Further exemplary results illustrating screening of Allosteramers for TNFR using TNF ⁇ -induced IL-6 synthesis assay in human fibroblasts (WI-38).
  • Exemplary peptides ALL-I through ALL-24 designed using Module X approach, herein defined, are shown here.
  • the sequences of the peptides are shown in Table 1.
  • an allosteric modulator is both a PAM and a NAM of a biological target.
  • an allosteric modulator is a Silent Allosteric Modulator (SAM) of a biological target, which binds to an allosteric site, but does not affect the function of a biological target.
  • SAM Silent Allosteric Modulator
  • Isolated refers to a substance and/or entity that has been (1) separated from at least some of the components with which it was associated when initially produced (whether in nature and/or in an experimental setting), and/or (2) produced, prepared, and/or manufactured by the hand of man. Isolated substances and/or entities may be separated from at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, about 99%, substantially 100%, or 100% of the other components with which they were initially associated.
  • isolated agents are more than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, substantially 100%, or 100% pure.
  • a substance is "pure” if it is substantially free of other components.
  • isolated cell refers to a cell not contained in a multi-cellular organism.
  • short peptides suitable for the inventive method are designed to contain a sequence having at least 70% (e.g., at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%) identical to the sequence of at least 5 (e.g., at least 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 18, 20, or 25) contiguous amino acids that appear in a target of interest. Percentage of amino acid sequence identity can be determined by alignment of amino acid sequences. Alignment of amino acid sequences can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, ALIGN or Megalign (DNASTAR) software.
  • TNF receptor 1 TNF receptor 1
  • TNFR2 TNF receptor 2
  • TNFRl TNF receptor 1
  • TNFR2 TNF receptor 2
  • TNFRl TNF receptor 1
  • TNFR2 TNF receptor 2
  • TNFRl TNF receptor 1
  • TNFR2 TNF receptor 2
  • TNFRl is a 75 kDa glycoprotein that has at least been shown to transduce cytotoxic and proliferative signals as well as signals resulting in the secretion of GM-CSF, IL-I and IL-6
  • TNFR2 is a 55 kDa glycoprotein that has at least been shown to transduce signals resulting in cytotoxic, anti-viral, and proliferative activities of TNF ⁇ .
  • Such flexible regions include, but are not limited to, juxtamembranous regions, regions containing ⁇ helix, ⁇ sheet, loops and/or ⁇ turns, regions between domains, regions between two ⁇ chains, and combinations thereof.
  • Various protein analysis tools are available to identify such flexible regions. For example, peptide sequences of TNF receptors can be systematically analyzed to identify regions that reproduce loops, hinge regions and other domains or secondary structures using software such as ProDom, PROSITE, or Predict Protein.
  • hydrophobic and flexible profiles can be examined using programs such as ProtScale.
  • flexible or other suitable regions can be identified based on crystallography, molecular modeling, and hydropathy profiles.
  • in vitro assays in accordance with the present invention can be carried out on high throughput platforms.
  • High throughput platforms are particularly useful for blind screenings to identify receptor modulators ⁇ e.g. , stimulators and/or inhibitors) from a large number of candidate or test peptides.
  • multiwell plates e.g., 24-, 48-, 96-, or 384-well plates, may be used for high throughput assays.
  • high throughput assays can be performed using an automated system so that candidate peptides may be provided and assays may be performed without human intervention.
  • Peptide modulators may be identified based on a receptor activity assay as compared to a control or reference.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Toxicology (AREA)
  • Immunology (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Zoology (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Cell Biology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne, notamment, des peptides courts (tels que des allostéramères™) capables de moduler efficacement les activités des récepteurs du TNF sur la base de séquences d'acide aminé de régions extracellulaires ou transmembranaires d'un récepteur du TNF. L'invention porte en outre sur de nouveaux procédés destinés à concevoir et à identifier des modulateurs de peptides. La présente invention concerne également des compositions pharmaceutiques contenant les peptides de la présente invention, et sur des utilisations thérapeutiques de celles-ci.
PCT/US2010/032310 2009-04-24 2010-04-23 Allostéramères pour récepteurs du tnf et utilisations afférentes WO2010124259A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US17253309P 2009-04-24 2009-04-24
US61/172,533 2009-04-24

Publications (1)

Publication Number Publication Date
WO2010124259A1 true WO2010124259A1 (fr) 2010-10-28

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Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/US2010/032310 WO2010124259A1 (fr) 2009-04-24 2010-04-23 Allostéramères pour récepteurs du tnf et utilisations afférentes
PCT/US2010/032315 WO2010124262A1 (fr) 2009-04-24 2010-04-23 Procédés d'identification d'allosteramers™ et leurs utilisations

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/US2010/032315 WO2010124262A1 (fr) 2009-04-24 2010-04-23 Procédés d'identification d'allosteramers™ et leurs utilisations

Country Status (1)

Country Link
WO (2) WO2010124259A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016187068A1 (fr) * 2015-05-15 2016-11-24 The General Hospital Corporation Anticorps antagonistes de la superfamille du récepteur du facteur de nécrose anti-tumoral
US10765700B2 (en) 2013-02-07 2020-09-08 The General Hospital Corporation Methods for expansion or depletion of t-regulatory cells
US11859002B2 (en) 2016-05-13 2024-01-02 The General Hospital Corporation Antagonistic anti-tumor necrosis factor receptor 2 antibodies

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL2657252T3 (pl) * 2010-12-23 2017-08-31 Hanall Biopharma Co., Ltd. Modyfikowany polipeptyd ludzkiego receptora-1 czynnika martwicy nowotworu lub jego fragment i sposób ich wytwarzania

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5447851A (en) * 1992-04-02 1995-09-05 Board Of Regents, The University Of Texas System DNA encoding a chimeric polypeptide comprising the extracellular domain of TNF receptor fused to IgG, vectors, and host cells
US20030108992A1 (en) * 2000-02-11 2003-06-12 Lenardo Michael J. Identification of a novel domain in the tumor necrosis factor receptor family that mediates pre-ligand receptor assembly and function
US20040180386A1 (en) * 2001-02-19 2004-09-16 Carr Francis J. Method for identification of t-cell epitopes and use for preparing molecules with reeduced immunogenicity
US7070783B1 (en) * 1995-05-09 2006-07-04 The Mathilda And Terence Kennedy Institute Of Rheumatology Small molecular weight TNF receptor multimeric molecule
US20070037210A1 (en) * 2002-10-24 2007-02-15 Sylvain Chemtob Cytokine receptor modulators, method of identifying same, and method of modulating cytokine receptors activity with same

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JP2003506411A (ja) * 1999-08-09 2003-02-18 トリペップ アクチ ボラゲット タンパク質重合阻害剤および使用方法
US7521530B2 (en) * 2002-06-11 2009-04-21 Universite De Montreal Peptides and peptidomimetics useful for inhibiting the activity of prostaglandin F2α receptor
JP2008542685A (ja) * 2005-05-05 2008-11-27 ヴァロリザーシヨン・アッシュエスジ，ソシエテ・アン・コマンディット サイトカイン受容体修飾因子及びその使用

Patent Citations (6)

* Cited by examiner, † Cited by third party
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US5447851A (en) * 1992-04-02 1995-09-05 Board Of Regents, The University Of Texas System DNA encoding a chimeric polypeptide comprising the extracellular domain of TNF receptor fused to IgG, vectors, and host cells
US5447851B1 (en) * 1992-04-02 1999-07-06 Univ Texas System Board Of Dna encoding a chimeric polypeptide comprising the extracellular domain of tnf receptor fused to igg vectors and host cells
US7070783B1 (en) * 1995-05-09 2006-07-04 The Mathilda And Terence Kennedy Institute Of Rheumatology Small molecular weight TNF receptor multimeric molecule
US20030108992A1 (en) * 2000-02-11 2003-06-12 Lenardo Michael J. Identification of a novel domain in the tumor necrosis factor receptor family that mediates pre-ligand receptor assembly and function
US20040180386A1 (en) * 2001-02-19 2004-09-16 Carr Francis J. Method for identification of t-cell epitopes and use for preparing molecules with reeduced immunogenicity
US20070037210A1 (en) * 2002-10-24 2007-02-15 Sylvain Chemtob Cytokine receptor modulators, method of identifying same, and method of modulating cytokine receptors activity with same

Non-Patent Citations (4)

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GRAY ET AL.: "Cloning of human tumor necrosis factor (TNF) receptor cDNA and expression of recombinant soluble TNF-binding protein.", PROC. NATL. ACAD. SCI. USA., vol. 87, no. 19, October 1990 (1990-10-01), pages 7380 - 7384 *
HWANG ET AL.: "A 20 amino acid synthetic peptide of a region from the 55 kDa human TNF receptor inhibits cytolytic and binding activities of recombinant human tumour necrosis factor in vitro.", PROC. BIOL. SCI., vol. 245, no. 1313, 22 August 1991 (1991-08-22), pages 115 - 119 *
MURALI ET AL.: "Disabling TNF receptor signaling by induced conformational perturbation of tryptophan-107.", PROC. NATL. ACAD. SCI. USA., vol. 102, no. 31, 2 August 2005 (2005-08-02), pages 10970 - 10975 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10765700B2 (en) 2013-02-07 2020-09-08 The General Hospital Corporation Methods for expansion or depletion of t-regulatory cells
US11844814B2 (en) 2013-02-07 2023-12-19 The General Hospital Corporation Methods for expansion or depletion of T-regulatory cells
WO2016187068A1 (fr) * 2015-05-15 2016-11-24 The General Hospital Corporation Anticorps antagonistes de la superfamille du récepteur du facteur de nécrose anti-tumoral
US10906982B2 (en) 2015-05-15 2021-02-02 The General Hospital Corporation Antagonistic anti-tumor necrosis factor receptor 2 antibodies
US11859002B2 (en) 2016-05-13 2024-01-02 The General Hospital Corporation Antagonistic anti-tumor necrosis factor receptor 2 antibodies

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