WO1999023259A1 - Composes antisens du recepteur du facteur de croissance de substances apparentees a l'insuline 1 - Google Patents

Composes antisens du recepteur du facteur de croissance de substances apparentees a l'insuline 1 Download PDF

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Publication number
WO1999023259A1
WO1999023259A1 PCT/US1998/023418 US9823418W WO9923259A1 WO 1999023259 A1 WO1999023259 A1 WO 1999023259A1 US 9823418 W US9823418 W US 9823418W WO 9923259 A1 WO9923259 A1 WO 9923259A1
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Prior art keywords
antisense oligonucleotide
seq
sequence
inter
nucleotides
Prior art date
Application number
PCT/US1998/023418
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English (en)
Inventor
Gerald Zon
Original Assignee
Inex Pharmaceutical Corporation
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.)
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Publication date
Application filed by Inex Pharmaceutical Corporation filed Critical Inex Pharmaceutical Corporation
Priority to AU13028/99A priority Critical patent/AU1302899A/en
Publication of WO1999023259A1 publication Critical patent/WO1999023259A1/fr

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    • 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
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1138—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against receptors or cell surface 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
    • 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
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/314—Phosphoramidates
    • C12N2310/3145—Phosphoramidates with the nitrogen in 3' or 5'-position
    • 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
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/315—Phosphorothioates

Definitions

  • the invention relates generally to oligonucleotides and their use as therapeutic agents, and more particularly, to the use of oligonucleotide antisense compounds directed to insulin-like growth factor- 1 receptor (IGF-1R) for treating certain cancers.
  • IGF-1R insulin-like growth factor- 1 receptor
  • the insulin-like growth factor- 1 receptor is a tyrosine kinase receptor with a 70% homology to the insulin receptor that plays a major role in cellular proliferation and maintenance.
  • it has been shown to be necessary for optimal cell growth, to be required for establishment and maintenance of a transformed phenotype, and to confer a protective effect against apoptotic cell death, e.g. Ullrich et al, EMBO J., 5: 2503-2512 (1986); Baserga, Cell, 79: 927-930 (1994); Baserga, Cancer
  • drugs or methods designed to block IGF-1R action may lead to therapies for a variety of cancers, including ovarian carcinoma, gliobastoma, and lung carcinoma, e.g. Ambrose et al, J. Cell. Physiol, 159: 92-100 (1994); Resnicoff et al, Laboratory Investigation, 69: 756-760 (1993); and Baserga et al, International patent application PCT/US94/03314.
  • antisense compounds directed to messenger RNA (mRNA) encoding IGF- 1R may lead to new anti-cancer drugs by down-regulating the expression of IGF-1R in tumor cells.
  • antisense approach is theoretically compelling in that one can readily identify candidate compounds once a gene sequence of the protein sought to be down regulated is available, practice has shown that antisense compounds directed to different sites on the same gene can lead to dramatically different results in assays designed to measure a biological end point, such as cell growth, specific protein synthesis, or the like, e.g. Zalewski et al, International patent application PCT/US 94/00264; .and Bennett et al, Adv. Pharmacol., 28: 1-43 (1994). Consequently, the antisense approach reduces but does not eliminate the need to screen large numbers of compounds to find drug candidates.
  • An objective of the invention is to provide methods and compounds for killing tumor cells while at the same time leaving normal cell populations unaffected.
  • Another objective of the invention is to provide methods for treating cancer, particularly ovarian carcinomas and glioblastomas.
  • a further objective of the invention is to provide an agent for inducing apoptosis in cells having an anchorage-independent growth phenotype.
  • Yet another objective of the invention is to provide antisense compounds capable of inhibiting the expression of IGF-1R in tumor cells.
  • the invention accomplishes these and other objectives by providing methods and compounds for inhibiting the expression of IGF-1R in tumor cells which, in turn, induces apoptosis.
  • the invention comprises antisense compounds specific for codons 4 to 9, inclusive, of human IGF-1R.
  • antisense compounds of the invention are oligonucleotides consisting of from 12 to 18 nucleotides. More preferably, antisense compounds of the invention consist of 5'-CCCTCCTCCGGAGCC-3' (SEQ ID NO: 1) or S'-GGACCCTCCTCCGGAGCCX (SEQ ID NO: 2).
  • the intemucleosidic linkages of antisense compound 5'-CCCTCCTCCGGAGCC-3' consist solely of N3'- P5' phosphoramidate linkages
  • the intemucleosidic linkages of antisense compound 5'-GGACCCTCCTCCGGAGCC-3' consist solely of phosphorothioate linkages.
  • antisense compound 5'- CCCTCCTCCGGAGCC-3' (SEQ ID NO: 1) has a 3' terminal hydroxyl group.
  • cognate refers to a nucleotide triplet of a messenger RNA that is translated into an amino acid during protein synthesis in accordance with the genetic code. Codons are numbered relative to the "start" codon which is taken as 1.
  • N3'-»P5' phosphoramidate refers to an intemucleosidic linkage of the form:
  • R 1 is hydrogen or a phosphate protecting group
  • X is a chalcogen, preferably oxygen or sulfur. More particularly, when R 1 is a phosphate protecting group it is hydrogen, methyl, or ⁇ - cyanoethyl.
  • nucleoside includes the natural nucleosides, including 2'-deoxy and 2'-hydroxyl forms, e.g. as described in Kornberg and B.aker, DNA Replication, 2nd Ed. (Freeman, San Fr.ancisco, 1992).
  • "Analogs” in reference to nucleosides includes synthetic nucleosides having modified base moieties and/or modified sugar moieties, e.g. described generally by Scheit, Nucleotide Analogs (John Wiley, New York, 1980). Such analogs include synthetic nucleosides designed to enhance binding properties, e.g. stability, specificity, or the like.
  • oligonucleotide includes linear oligomers of natural or . modified monomers or linkages, including deoxyribonucleosides, ribonucleosides, ⁇ - anomeric forms thereof, poly-amide nucleic acids, and the like, capable of specifically binding to a target polynucleotide by way of a regular pattern of monomer-to-monomer interactions, such as Watson-Crick type of base pairing.
  • monomers are linked by phosphodiester bonds or analogs thereof to form oligonucleotides ranging in size from a few monomeric units, e.g. 3-4, to several tens of monomeric units.
  • oligonucleotide is represented by a sequence of letters, such as "ATGUCCTG,” it will be understood that the nucleotides are in 5X3' order from left to right and that "A” denotes deoxyadenosine, “C” denotes deoxycytidine, “G” denotes deoxyguanosine, “T” denotes thymidine, and “U” denotes deoxyuridine, unless otherwise noted.
  • Analogs of phosphodiester linkages include phosphorothioate, phosphorodithioate, phosphoramidate, and the like, as more fully described below.
  • antisense compound or the term “antisense oligonucleotide” means an oligonucleotide designed to prevent or inhibit the expression of a gene by specifically hybridizing to its mRNA.
  • apoptosis refers to the phenomena of programmed cell death or suicide which characterized by a variety of molecular, physiological, and morphological changes in a cell, including chromatin condensation, internucleosomal DNA cleavage (resulting in the hallmark DNA laddering), cytoskeletal disruption, cell shrinkage, and membrane blebbing.
  • chromatin condensation resulting in the hallmark DNA laddering
  • cytoskeletal disruption resulting in the hallmark DNA laddering
  • cell shrinkage cell shrinkage
  • membrane blebbing membrane blebbing.
  • the invention is directed to antisense compounds specific for the region of human IGF-1R bound by codons 4 to 9, inclusive. Antisense compounds directed to this region have been discovered to be significantly more effective in inducing apoptosis in tumor cells than other .antisense compounds.
  • Antisense compounds of the invention comprise .any polymeric compound capable of specifically binding to a target polynucleotide by way of a regular pattern of monomer- to-nucleoside interactions, such as Watson-Crick type of base pairing.
  • Antisense compounds of the invention may also contain pendent groups or moieties, either as part of or separate from the basic repeat unit of the polymer, to enhance specificity, nuclease resistance, delivery, or other properties related to efficacy, e.g. cholesterol moieties, duplex intercalators such as acridine, poly-L-lysine, "end capping" with one or more nuclease- resisant linkage groups such as phosphorothioate, and the
  • nuclease resistance is conferred on the antisense compounds of the invention by providing nuclease-resistant intemucleosidic linkages.
  • nuclease-resistant intemucleosidic linkages are known in the art and are described in many reviews, e.g. Uhlmann and Peyman,
  • antisense compounds of the invention have intemucleosidic linkages selected from the group consisting of phosphodiester, phosphorothioate, or phosphoramidate, particularly, N3'— »P5' phosphoramidate.
  • Antisense compounds of the invention may also include nucleoside modifications, such as 2'-O-alkyl-substituted ribonucleosides, Altmann et al, Biochemical Society Transactions, 24: 630-637 (1996); 5-propynyl modificated pyrimidines, Froehler et al, Tetrahedron Lett., 33: 5307-5310 (1992); Beaucage and Iyer, Tetrahedron, 48: 2223-2311 (1992); Molko et al, U.S. patent 4,980,460; Koster et al, U.S. patent 4,725,677; Caruthers et al, U.S.
  • antisense compounds of the invention are synthesized by conventional means on commercially available automated DNA synthesizers, e.g. an Applied Biosystems (Foster City, CA) model 380B, 392 or 394 DNA/RNA synthesizer.
  • Applied Biosystems Foster City, CA
  • oligonucleotide moieties is sufficiently large to ensure that specific binding will take place only at the desired target polynucleotide and not at other fortuitous sites, as explained in many references, e.g. Rosenberg et al, International application PCT US92/05305; or Szostak et al, Meth. Enzymol. 68: 419-429 (1979).
  • the upper range of the length is determined by several factors, including the inconvenience and expense of synthesizing and purifying oligomers greater than about 30-40 nucleotides in length, the greater tolerance of longer oligonucleotides for mismatches than shorter oligonucleotides, whether modifications to enhance binding or specificity are present, whether duplex or triplex binding is desired, the enhancement or reduction in duplex or triplex stability imparted by a particular analog, and tfye like.
  • antisense compounds consisting solely of N3'-»P5' phosphoramidate linkages have lengths in the range of about 12 to 15 nucleotides.
  • the antisense oligonucleotides of the invention are employed as one or more components of pharmaceutical compositions.
  • Components of pharmaceutical compositions of the invention depend on several factors, including the nature of the disease or condition being treated, the location of disease lesions, the mode of drug delivery .and/or administration contemplated, the latter of which can include in vivo administration by way of a catheter into a target lesion or organ, topical application, intranasal administration, administration by implanted or transdermal sustained release systems, and the like.
  • compositions of the invention include a pharmaceutical carrier that may contain a variety of components that provide a variety of functions, including regulation of drug concentration, regulation of solubility, chemical stabilization, regulation of viscosity, absorption enhancement, regulation of pH, and the like.
  • a pharmaceutical carrier that may contain a variety of components that provide a variety of functions, including regulation of drug concentration, regulation of solubility, chemical stabilization, regulation of viscosity, absorption enhancement, regulation of pH, and the like.
  • the pharmaceutical composition preferably includes a buffer such as a phosphate buffer, or other organic acid salt, preferably at a pH of between about 7 and 8.
  • a nonionic surfactant such as Tween 80 in an amount of 0.04-0.05% (w/v), to increase solubility.
  • antioxidants such as ascorbic acid
  • hydrophilic polymers such as, monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, dextrins, chelating agents, such as EDTA, and like components well known to those in the pharmaceutical sciences, e.g. Remington's Pharmaceutical Science, latest edition (Mack Publishing Company, Easton, PA).
  • Antisense compounds of the invention include the pharmaceutically acceptable salts thereof, including those of alkaline earths, e.g. sodium or magnesium, ammonium or N 4 + , wherein X is C- -C4 alkyl.
  • Other pharmaceutically acceptable salts include org-anic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic, and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, and benzenesulfonic; and inorganic acids such as hydrochloric, sulfuric, phosphoric, and sulfamic acids.
  • Pharmaceutically acceptable salts of a compound having a hydroxyl group include the anion of such compound in combination with a suitable cation such as Na + , NH4 + , or the like.
  • Sustained release systems suitable for use with the pharmaceutical compositons of the invention include semi-permeable polymer matrices in the form of films, microcapsules, or the like, comprising polylactides, copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, poly(2 : hydroxyethyl methacrylate), and like materials, e.g. Rosenberg et al, International application PCT/US92/05305.
  • Sustained release systems also include liposomally entrapped antisense compounds, e.g. as described in Liposome Technology, Vol. LI, Incorporation of Drugs, Proteins, an Genetic Material (CRC Press).
  • an effective amount of IGF-1R antisense oligonucleotide for particular applications depends on several factors, including the chemical nature of the antisense oligonucleotide, the disorder being treated, the method of administration, the stability of the complex between the antisense compound and its target, and the like.
  • an effective amount will provide a concentration of IGF-1R antisense oligonucleotide of between about 1 to 100 ⁇ M at the target polynucleotide; and more preferably, an effective amount will provide a concentration of antisense oligonucleotide of between about 1 to 10 ⁇ M at the target polynucleotide.
  • Antisense compounds of the invention are selected on the basis of an in vivo diffusion chamber assay for apoptosis described in Resnicoff et al, Cancer Research 55: 2463-2469 (1995).
  • the sequence of human IGF-1R is disclosed in Baserga et al, U.S. patent 5,643,788, which patent is incorporated by reference. Briefly, diffusion chambers are constructed from 14-mm Lucite rings with 0.1 ⁇ m pore-sized hydrophilic Durapore membranes (Millipore, Bedford, MA). The chambers are sterilized with ethylene oxide prior to use. Cells of a test population are preincubated with an antisense compound for 24 hr.
  • mice e.g., strain C57B 1/6
  • .anesthesia e.g. Halothane, or the like.
  • cells are placed into a diffusion chamber, inserted in the subcutaneous tissue of a test animal, and the antisense compound is injected into the subcutaneous tissue adjacent to the chamber, e.g. 0.2 mg in 0.15 ml.
  • either sense or random sequence oligonucleotides are used as controls.
  • the cells are washed with PBS -and treated with RNase A (75 units/ml) for 30 min. at 37°C, washed again in PBS, and resuspended in PBS containing 15 ⁇ g/ml propidium iodide.
  • Cells are then analyzed by flow cytometry, e.g. Coulter Epics Profile U (Coulter Electronics, Inc., Hialeah, FL), or like instrument.
  • IGF-1R antisense compounds were determined in several tumor cell lines using the diffusion chamber assay with the following results:
  • Toxicity analysis included observations of the hematological states, standard clinical chemistry, histology, -and weight .and mo ⁇ hology of org.ans of all test animals. There were no apparent test article-related clinical observations for male and female mice administered LR4437 by repeated dose up to 300 mg kg.

Abstract

L'invention concerne un procédé et des composés servant à inhiber l'expression du récepteur du facteur de croissance de substances apparentées à l'insuline 1 dans des cellules tumorales. Un aspect important de l'invention concerne la découverte selon laquelle les composés antisens de l'invention constituent de puissants inducteurs d'apoptose préférentielle de cellules tumorales. Des composés antisens de l'invention concernent les codons 4 à 9 d'ARN messager codant pour le récepteur du facteur de croissance de substances apparentées à l'insuline 1.
PCT/US1998/023418 1997-11-04 1998-11-03 Composes antisens du recepteur du facteur de croissance de substances apparentees a l'insuline 1 WO1999023259A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU13028/99A AU1302899A (en) 1997-11-04 1998-11-03 Antisense compounds to insulin-like growth factor-1 receptor

Applications Claiming Priority (2)

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US96388697A 1997-11-04 1997-11-04
US08/963,886 1997-11-04

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WO1999023259A1 true WO1999023259A1 (fr) 1999-05-14

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000009145A1 (fr) * 1998-08-13 2000-02-24 Thomas Jefferson University Traitement de tumeurs au moyen d'oligonucleotides agissant sur le recepteur du facteur de croissance insulunoide i
US6312684B1 (en) 1994-11-16 2001-11-06 Thomas Jefferson University Method of inducing resistance to tumor growth
US6340674B1 (en) 1993-03-26 2002-01-22 Thomas Jefferson University Method of inhibiting the proliferation and causing the differentiation of cells with IGF-1 receptor antisense oligonucleotides
US6541036B1 (en) 1997-05-29 2003-04-01 Thomas Jefferson University Treatment of tumors with oligonucleotides directed to insulin-like growth factor-I receptors (IGF-IR)
WO2004072284A1 (fr) * 2003-02-11 2004-08-26 Antisense Therapeutics Ltd Modulation de l'expression du recepteur du facteur de croissance i analogue a l'insuline
WO2010146059A2 (fr) 2009-06-16 2010-12-23 F. Hoffmann-La Roche Ag Biomarqueurs pour une thérapie par inhibiteur d'igf-1r

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994022486A1 (fr) * 1993-03-26 1994-10-13 Thomas Jefferson University Procede d'inhibition de la proliferation cellulaire et de declenchement de la differenciation des cellules a l'aide d'oligonucleotides antisens du recepteur du facteur de croissance de type 1

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994022486A1 (fr) * 1993-03-26 1994-10-13 Thomas Jefferson University Procede d'inhibition de la proliferation cellulaire et de declenchement de la differenciation des cellules a l'aide d'oligonucleotides antisens du recepteur du facteur de croissance de type 1
US5643788A (en) * 1993-03-26 1997-07-01 Thomas Jefferson University Method of inhibiting the proliferation and causing the differentiation of cells with IGF-1 receptor antisense oligonucleotides

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
RESNICOFF M, ET AL.: "INHIBITION OF RAT C6 GLIOBLASTOMA TUMOR GROWTH BY EXPRESSION OF INSULIN-LIKE GROWTH FACTOR I RECEPTOR ANTISENSE MRNA", CANCER IMMUNOLOGY AND IMMUNOTHERAPY, SPRINGER-VERLAG, BERLIN, DE, vol. 42, 1 January 1996 (1996-01-01), BERLIN, DE, pages 64 - 68, XP002916893, ISSN: 0340-7004, DOI: 10.1007/s002620050252 *
RESNICOFF M, ET AL.: "RAT GLIOBLASTOMA CELLS EXPRESSING AN ANTISENSE RNA TO THE INSULIN-LIKE GROWTH FACTOR-1 (IGF-1) RECEPTOR ARE NONTUMORIGENIC AND INDUCE REGRESSION OF WILD-TYPE TUMORS", CANCER RESEARCH, AMERICAN ASSOCIATION FOR CANCER RESEARCH, US, vol. 54, 15 April 1994 (1994-04-15), US, pages 2218 - 2222, XP002916892, ISSN: 0008-5472 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6340674B1 (en) 1993-03-26 2002-01-22 Thomas Jefferson University Method of inhibiting the proliferation and causing the differentiation of cells with IGF-1 receptor antisense oligonucleotides
US6312684B1 (en) 1994-11-16 2001-11-06 Thomas Jefferson University Method of inducing resistance to tumor growth
US6506415B2 (en) 1994-11-16 2003-01-14 Thomas Jefferson University Method of inducing resistance to tumor growth
US6541036B1 (en) 1997-05-29 2003-04-01 Thomas Jefferson University Treatment of tumors with oligonucleotides directed to insulin-like growth factor-I receptors (IGF-IR)
WO2000009145A1 (fr) * 1998-08-13 2000-02-24 Thomas Jefferson University Traitement de tumeurs au moyen d'oligonucleotides agissant sur le recepteur du facteur de croissance insulunoide i
WO2004072284A1 (fr) * 2003-02-11 2004-08-26 Antisense Therapeutics Ltd Modulation de l'expression du recepteur du facteur de croissance i analogue a l'insuline
JP2006520586A (ja) * 2003-02-11 2006-09-14 アンチセンス セラピューティクス リミテッド インスリン様増殖因子ｉ受容体発現の調節
US7468356B2 (en) 2003-02-11 2008-12-23 Antisense Therapeutics Ltd. Modulation of insulin like growth factor I receptor expression
JP4753863B2 (ja) * 2003-02-11 2011-08-24 アンチセンス セラピューティクス リミテッド インスリン様増殖因子ｉ受容体発現の調節
US8217017B2 (en) 2003-02-11 2012-07-10 Antisense Therapeutics Limited Modulation of insulin like growth factor I receptor expression
WO2010146059A2 (fr) 2009-06-16 2010-12-23 F. Hoffmann-La Roche Ag Biomarqueurs pour une thérapie par inhibiteur d'igf-1r

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