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WO1998003538A3 - Signal-regulated, cleavage-mediated toxins - Google Patents

Signal-regulated, cleavage-mediated toxins Download PDF

Info

Publication number
WO1998003538A3
WO1998003538A3 PCT/US1997/010941 US9710941W WO9803538A3 WO 1998003538 A3 WO1998003538 A3 WO 1998003538A3 US 9710941 W US9710941 W US 9710941W WO 9803538 A3 WO9803538 A3 WO 9803538A3
Authority
WO
WIPO (PCT)
Prior art keywords
domain
sitoxin
cleavage
effector domain
target cell
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US1997/010941
Other languages
French (fr)
Other versions
WO1998003538A2 (en
Inventor
Alexander Varshavsky
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
California Institute of Technology
Original Assignee
California Institute of Technology
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 California Institute of Technology filed Critical California Institute of Technology
Publication of WO1998003538A2 publication Critical patent/WO1998003538A2/en
Publication of WO1998003538A3 publication Critical patent/WO1998003538A3/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/62—DNA sequences coding for fusion proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/09—Fusion polypeptide containing a localisation/targetting motif containing a nuclear localisation signal
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/50—Fusion polypeptide containing protease site
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/55—Fusion polypeptide containing a fusion with a toxin, e.g. diphteria toxin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/95—Fusion polypeptide containing a motif/fusion for degradation (ubiquitin fusions, PEST sequence)

Landscapes

  • Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Wood Science & Technology (AREA)
  • General Health & Medical Sciences (AREA)
  • Zoology (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Physics & Mathematics (AREA)
  • Botany (AREA)
  • Plant Pathology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Microbiology (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Disclosed is a novel class of molecules referred to herein as sitoxins (signal-related, cleavage-mediated toxins. A sitoxin combines several functional domains to produce a therapeutically effective molecule. More specifically, a sitoxin is comprised of an effector domain; a domain bearing an intracellular signalling moiety; and a domain located between the effector domain and the domain bearing the intracellular signalling moiety which specifies a cleavage site for a predetermined protease. Also disclosed are methods for selectively killing a target cell which is known to contain a predetermined protease. Such methods involve the introduction of a sitoxin into a target cell. The sitoxin can be introduced directly, or through the intermediacy of an expression vector. Following the introduction of the sitoxin into the target cell, cleavage by the predetermined protease separates the effector domain of the sitoxin from the intracellular signalling moiety, resulting either in a longer-lived (and therefore more toxic) effector domain or in an effector domain that moves from a cellular compartment where the domain is nontoxic to a cellular compartment where the domain is able to exert its effect.
PCT/US1997/010941 1995-10-27 1997-10-24 Signal-regulated, cleavage-mediated toxins Ceased WO1998003538A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US54927595A 1995-10-27 1995-10-27
US08/549,275 1995-10-27

Publications (2)

Publication Number Publication Date
WO1998003538A2 WO1998003538A2 (en) 1998-01-29
WO1998003538A3 true WO1998003538A3 (en) 1998-03-26

Family

ID=24192333

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/010941 Ceased WO1998003538A2 (en) 1995-10-27 1997-10-24 Signal-regulated, cleavage-mediated toxins

Country Status (2)

Country Link
CA (1) CA2236036A1 (en)
WO (1) WO1998003538A2 (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69926647T2 (en) * 1998-10-16 2006-11-09 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. MOLECULAR PATHOGENICIDE-MEDIATED DISEASE RESISTANCE IN PLANTS
WO2000050089A2 (en) * 1999-02-26 2000-08-31 Mindset Biopharmaceuticals (Usa) Ltd. Regulation of the stability of recombinant proteins and antiboodies
WO2012139112A1 (en) * 2011-04-08 2012-10-11 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Ubiquitin fusions for improving the efficacy of cytosolic acting targeted toxins

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BIOCONJUGATE CHEM., 1993, Vol. 4, COOK J.P. et al., "Biologically Active Interleukin 2-Ricin A Chain Fusion Proteins May Require Intracellular Proteolytic Cleavage to Exhibit a Cytotoxic Effect", pages 440-447. *
EUR. J. BIOCHEM., 1991, Vol. 199, LOUIS J.M. et al., "Autoprocessing of the HIV-1 Protease Using Purified Wild-Type and Mutated Fusion Proteins Expressed at High Levels in Escherichia Coli", pages 361-369. *

Also Published As

Publication number Publication date
CA2236036A1 (en) 1998-01-29
WO1998003538A2 (en) 1998-01-29

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