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WO2004054657A1 - Therapie contre le cancer a base d'oligonucleotides antisens combines - Google Patents

Therapie contre le cancer a base d'oligonucleotides antisens combines Download PDF

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Publication number
WO2004054657A1
WO2004054657A1 PCT/EP2003/014043 EP0314043W WO2004054657A1 WO 2004054657 A1 WO2004054657 A1 WO 2004054657A1 EP 0314043 W EP0314043 W EP 0314043W WO 2004054657 A1 WO2004054657 A1 WO 2004054657A1
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WO
WIPO (PCT)
Prior art keywords
seq
antisense
bcl
plkl
therapy
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Application number
PCT/EP2003/014043
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German (de)
English (en)
Inventor
Vera Elez
Original Assignee
Vera Elez
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 Vera Elez filed Critical Vera Elez
Priority to AU2003292227A priority Critical patent/AU2003292227A1/en
Publication of WO2004054657A1 publication Critical patent/WO2004054657A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7125—Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7115—Nucleic acids or oligonucleotides having modified bases, i.e. other than adenine, guanine, cytosine, uracil or thymine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Cancer therapies traditionally include radiation and chemotherapy in addition to surgical tumor removal. While surgical removal and radiation therapy are only possible in the case of precisely localized diseases, chemotherapy can also be used to treat metastatic cancers. However, chemotherapy is generally not a very specific form of treatment, which on the one hand leads to strong or hardly tolerable side effects and on the other hand only has a limited effectiveness.
  • the inhibition of gene expression by asOe can be carried out in at least four ways:
  • the mRNA-DNA hybrids formed are cut up by RNase H, the polyadenylation or the transport of the finished mRNA into the cytoplasm can be inhibited by asOe, the initiation of mRNA translation can, for example, by Interference with the construction of the ribosomal complex can be inhibited and finally protein elongation can be sterically prevented by the bound asO.
  • the asOe in order to be able to develop their effects, the asOe must be stable enough to withstand early degradation in the organism and secondly they must be able to reach their place of action within the cell or within the cell nucleus.
  • genes against which asO therapy is already in clinical trials include c-Raf-1 kinase (ISIS 5132, ISIS / Novartis), Bcl-2 (G3139, Genta) and H-Ras (ISIS 2503, SIS ).
  • c-Raf-1 is a serine / threonine kinase that plays an important role in cell growth and survival.
  • Gokhale et al. (1999, Antisense Nucl. Acid Drug Dev. 9, 191-201) report that treatment of tumors with asOen against c-Raf-1 leads to inhibition of tumor growth but not to regression of the tumors.
  • Plkl is overexpressed in over 90% of all human carcinomas, which is associated with increased mitotic activity and a poor prognosis (Wolf et. Al., 1997, Oncogene 14, 543-9; Knecht et al., 1999, Cancer Res. 59, 2794 -7). Impairment of Plkl function in cancer cells leads to abnormal mitosis with subsequent mitotic cell death (Lane and Nigg, 1995, J. Cell Biol. 2, 1701-13), therefore Plk-1 represents a potentially interesting target for asO cancer therapy. Elez et al. (2000, Biochem. Biophys. Res. Comm. 269, 352-6 and DE 100 11 530 A1) report a significant reduction in tumors in a human tumor xenograft mouse model after prolonged treatment with Plk1-asO. However, complete remission could not be achieved.
  • the corresponding antisense oligonucleotides can be administered simultaneously or alternately. When administered simultaneously, the corresponding antisense oligonucleotides can be present together in a pharmaceutical formulation or else can be formulated separately.
  • the corresponding antisense oligonucleotides are administered together twice a week.
  • the corresponding antisense oligonucleotides are administered alternately once a week, ie first the asO, a few days later the second, so that asOe are administered twice a week, but each individually and therefore once a week.
  • the asOe are preferably in one Amount of approximately 5 mg / kg body weight administered, it being clear that it is the responsibility of the doctor to adjust the dose and the number of administrations in each specific case depending on the patient, the disease or the medical history.
  • the antisense oligonucleotides are preferably short-chain deoxyribonucleic acids with a length of 10-55 bases, preferably 12-40 and very particularly preferably 15-30.
  • the antisense oligodeoxynucleotides are preferably modified against enzymatic degradation.
  • the substituents known in the prior art either individually or in combination, are suitable as modifications. Suitable modifications are the incorporation of phosphotriester, phosphoramide, methylphosphonate, phosphorothioate and peptide nucleic acid bonds into the structure of the oligonucleotides. Because of its increased stability and the ability to trigger RNase H activity, phosphorothioate-modified asOe are particularly preferred.
  • the asOe directed against Plkl are preferably directed against human Plkl.
  • the corresponding preferred gene according to the invention can be found at Genebank Acc. No .: NT_010604, from bp 635298 - 646820.
  • the corresponding mRNA sequence can be found under Genebank Acc. No .: X73458.
  • the asOe directed against Bcl-2 are preferably directed against human Bcl-2.
  • the corresponding gene preferred according to the invention can be found (complementarily) under the Genebank Acc. No .: NT_033907, bp 4363332 - 4559938.
  • the corresponding mRNA sequence can be found under Genebank Acc. No .: M13994, as well as M14745, the Genebank Acc. No. the splice variant a is NM_000633 and the splice variant ß is NM_000657.
  • the medicament according to the invention is preferably used for the therapy of cancer cells which overexpress Plkl, Bcl-2 or both genes.
  • FIG. 1 Antisense oligonucleotides down-regulate Plkl expression in A549 cells.
  • A549 cells were treated with Dotap lipofection with JWG160 (SEQ ID No .: 4) or JWG370 (SEQ ID No .: 6) antisense oligonucleotides (1 ⁇ M each). After 48 h of incubation, the total protein was extracted and examined by Western blot analysis. Control: untreated cells. Dotap: lipofection only. JWG160-MM and JWG370-MM: corresponding mismatch oligonucleotides (SEQ ID No .: 20 and SEQ ID No .: 21).
  • Figure 2 Inhibition of proliferation by anti-PIkl (JWG160; SEQ ID No .: 4) and anti-Bcl-2 (G3139; SEQ ID No .: 19) oligonucleotides.
  • Figure 3 Fluorescence micrographs of MDA-MB-435 xenografts with FITC-labeled antisense oligonucleotides.
  • Figure 4 Antitumor activity of anti-PIkl (JWG160; SEQ ID No .: 4) and anti-Bcl-2 (G3139; SEQ ID No .: 19) oligonucleotides in NMRI nude mice, the A549, MDA-MB-435, Detroit562 and primary abdominal cancer tumors.
  • Antisense oligonucleotides (G3139 and JWG160) were administered intravenously twice a week or as a successive combination in doses of 5 mg / kg by bolus injection. Five minutes after administration of the asOe, five high-voltage pulses were administered to the tumor (400 V / cm 2 , at 10 ms intervals). After four weeks of treatment, the mice were sacrificed, the tumors were prepared and the tumor mass was determined using a precision balance. (a) Inhibition of tumor growth of A549 tumors by therapy with G3139 and JWG160 asOen and electroporation. (b) Inhibition of tumor growth of Detroit562 tumors by therapy with G3139 and JWG160 asOen and electroporation.
  • FIG. 5 Electroporation-supported treatment with anti-PIkl (JWG160; SEQ ID No .: 4) and anti-Bcl-2 (G3139; SEQ ID No .: 19) oligonucleotides inhibits MDA-MB-435 tumor growth in vivo.
  • JWG160 Antisense against Plkl with electroporation (5 x 400 V / cm 2 for 10 ms, twice a week for 4 weeks).
  • JWG160 & G3139 combination therapy with asOen against Plkl and Bcl-2 using the identical electrical pulse regime, (a) photograph of the removed tumors after 4 weeks of electroporation-assisted antisense therapy. Control: untreated animals. Electro: electroporation without the use of asOen.
  • the protein extracts of each individual lane were obtained from different tumors and analyzed by means of anti-PIkl and anti-Bcl-2 immunoblotting and with anti-ß-actin reprobed.
  • the oligonucleotides were produced using an automatic DNA synthesizer (Perseptive 8909; BioSpring GmbH; Frankfurt) using a method known in the art.
  • the phosphorothiaot backbone of the oligonucleotides was completely modified.
  • the oligonucleotides were treated with concentrated ammonia for 16 hours at room temperature.
  • the oligonucleotides were then purified by "reverse phase” chromatography and lyophilized. The lyophilizate was precipitated twice with 1 M NaCl / ethanol and lyophilized again.
  • the radioactive labeling of the antisense strands was carried out with the following primers: PlklAs: 5'-TGA TGT TGG CAC CCT TTC AGC-3 ', GAPDH: sense: 5'-CAC CCA TGG CAA ATT CCA TG-3 ⁇ antisense: 5 -'CAT GGT TCA CAC CCA TGA CG-3 '.
  • Hybridization was carried out in QuickHyb solution (Stratagene, La Jolla, CA, USA) for 1 hour at 68 ° C.
  • the cellular proteins were used using 250 ⁇ l of Rl PA buffer (1 ⁇ PBS, 1% Nonidet P-0, 0.5% sodium deoxycholate,
  • the blots were incubated for 30 min at 50jC in stripping buffer (62.5 mM Tris-HCl, pH 6.7, 2% SDS and 100 mM ⁇ -mercaptoethanol), extensively with
  • Example 4 Treatment of human (cancer) cell lines with antisense oligonucleotides.
  • the human cancer cell lines A549, Detroit562 and MDA-MB-435 used in cell culture were acquired from the American Type Culture Collection (ATCC) and the German Collection of Microorganisms and Cell Cultures.
  • DMEM Dulbecco's Modified Eagle's Medium
  • FCS heat-inactivated fetal calf serum
  • the oligonucleotide-containing medium was replaced by normal cell culture medium (10% FCS) and the cells were incubated for a further 24 or 48 hours.
  • the viability of the cells was determined by staining with trypan blue (0.1%), the number of trypan blue negative cells being determined by counting in a counting chamber.
  • Transfected cells treated only with Dotap showed 95 to 100% viability 24 hours after the transfection.
  • JWG370-MM 5'-GAT CAG TCC ACG TTG TG-3 '(SEQ ID No .: 21)
  • G3139-MM 5'-TCT CTC AGC ATG TGC TAT-3 '(SEQ ID No .: 22)
  • Effects directed against cell proliferation were determined by daily determination of the cell number and viability by direct counting using the trypan blue method.
  • the viability of the cells was determined daily for 4 days after treatment with the respective antisense oligonucleotide.
  • the cells were suspended in 0.1% trypan blue and counted. At each point in time, the mean was taken from three counts and the percentage of viable cells was calculated.
  • the animal studies were carried out in groups with 5-6 nude, eight to ten week old Athymie mice (nu / nu) NMRI (Harlan Winkelmann, Borchen). 2x10 6 A549, Detroit562, MDA-MB-435 and primary abdominal cancer cells were injected subcutaneously and subjected to at least three successive transplants before antisense treatment was started. Tumor fragments of approximately 20 to 25 mg were implanted subcutaneously into the left and right side of the animal under anesthetic with urethane. The antisense oligonucleotide treatments started when the tumors reached an average volume of 60 to 90 mm 3 (7 to 14 days after the transplant).
  • Antisense oligonucleotides (G3139 and JWG160) were administered intravenously into the tail vein twice a week or as a successive combination in doses of 5 mg / kg by bolus injection (200 ⁇ l). Five minutes after administration of the asOe, five high voltage pulses were administered percutaneously to the tumor. For this purpose, two steel electrodes were placed percutaneously in parallel on opposite sides of the tumor using contact paste and 5 successive rectangular pulses of 400 V / cm 2 of 10 ms duration were administered to the tumor. There was an interval of 1 s between each pulse. After four weeks of treatment, the mice were sacrificed, the tumors were prepared and the tumor mass was determined using a precision balance.
  • the animals were monitored by general clinical examinations, body weight and tumor growth.
  • oligonucleotides bind to serum albumin and alpha 2 macroglobulin and show biphasic pharmacokinetics (Agrawal et al., 1991, Proc. Natl. Acad. Sci. USA, 88, 7595-99).
  • oligonucleotide biodistribution showed that intravenously, subcutaneously or intraperitoneally administered oligonucleotides accumulate mainly in the liver, kidneys or other organs of the reticuloendothelial system (Agrawal et al., 1991, Proc. Natl. Acad. Sci. USA, 88, 7595- 99).
  • Fluorescin isothiocyanate (FITC) labeled phosphorothioate oligonucleotides were injected intravenously into nude mice. After five minutes, the tumors were electropermeabilized as described in Example 6. 24 hours later, the tumors were dissected and frozen at -70jC. Five-micron sections were examined by fluorescence microscopy.
  • FITC Fluorescin isothiocyanate
  • Example 8 Immunohistochemical studies, apoptosis assay, mouse tissue and tumors from NMRI nude mice were examined histologically by hematoxylin and eosin staining. Proliferating cells were visualized by staining with Ki67 antibodies (DAKO, Hamburg) and blood vessels were stained with antibodies against von Willebrand factor (vWF). Frozen sections (5 ⁇ m) were fixed in acetone (-20jC, 2 min). The tissue sections were then washed in Tris-buffered saline (TBS) and incubated with the polyclonal rabbit anti-mouse Ki67 antibody (1:25) or the rabbit antiMaus vWF antibody (1: 100) for 60 s at 37 ° C.
  • Ki67 antibodies DAKO, Hamburg
  • vWF von Willebrand factor

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  • Health & Medical Sciences (AREA)
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Abstract

Thérapie contre le cancer à base d'oligonucléotides antisens combinés, fondée sur l'utilisation d'un oligodésoxynucléotide antisens dirigé contre la kinase 1 de type polo (Plk1) en combinaison avec un oligodésoxynucléotide antisens dirigé contre le proto-oncogène 2 de la leucémie/lymphome à lymphocytes B (Bcl-2).
PCT/EP2003/014043 2002-12-13 2003-12-11 Therapie contre le cancer a base d'oligonucleotides antisens combines WO2004054657A1 (fr)

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Application Number Priority Date Filing Date Title
AU2003292227A AU2003292227A1 (en) 2002-12-13 2003-12-11 Combined antisense oligonucleotide cancer therapy

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DE10258677.2 2002-12-13
DE10258677A DE10258677A1 (de) 2002-12-13 2002-12-13 Kombinations-antisense-Oligonukleotid-Krebstherapie

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1546179A4 (fr) * 2002-07-30 2007-12-19 Isis Pharmaceuticals Inc Modulation antisens de l'expression de kinase de type polo
WO2007089367A3 (fr) * 2005-12-27 2008-10-09 Genentech Inc Procedes d'utilisation d'antagonistes de kinase hedgehog permettant d'inhiber la signalisation hedgehog et de traiter les troubles dont la mediation est assuree par hedgehog
RU2413519C2 (ru) * 2005-05-17 2011-03-10 Чанчунь Хуапу Байотекнолоджи Ко., Лтд. Олигонуклеотиды или их функциональные гомологи, содержащая их композиция и способ лечения в-клеточной опухоли
WO2021155073A1 (fr) * 2020-01-29 2021-08-05 Cardiff Oncology, Inc. Traitement de leucémies et de lymphomes avec des combinaisons d'inhibiteurs de bcl-2 et d'inhibiteurs de plk1

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WO2000061810A1 (fr) * 1999-04-08 2000-10-19 Oasis Biosciences, Inc. Oligonucleotides anti-sens contenant des bases universelles et/ou degenerees
WO2000066724A2 (fr) * 1999-04-30 2000-11-09 Universität Zürich Derives d'oligonucleotides diriges contre les arn messagershumains bcl-xl et bcl-2
WO2002017852A2 (fr) * 2000-08-25 2002-03-07 Genta Incorporated Methodes de traitement d'une pathologie en rapport avec le gene bcl-2 au moyen d'oligomeres antisens de bcl-2
US6414134B1 (en) * 1988-12-22 2002-07-02 The Trustees Of The University Of Pennsylvania Regulation of bcl-2 gene expression
WO2002057480A2 (fr) * 2001-01-22 2002-07-25 Genta Incorporated Methodes et compositions destinees a traiter un trouble associe a la proliferation cellulaire au moyen d'oligomeres leurres cre, d'oligomeres antisens bcl-2 et d'oligomeres hybrides correspondants

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US6414134B1 (en) * 1988-12-22 2002-07-02 The Trustees Of The University Of Pennsylvania Regulation of bcl-2 gene expression
WO2000061810A1 (fr) * 1999-04-08 2000-10-19 Oasis Biosciences, Inc. Oligonucleotides anti-sens contenant des bases universelles et/ou degenerees
WO2000066724A2 (fr) * 1999-04-30 2000-11-09 Universität Zürich Derives d'oligonucleotides diriges contre les arn messagershumains bcl-xl et bcl-2
WO2002017852A2 (fr) * 2000-08-25 2002-03-07 Genta Incorporated Methodes de traitement d'une pathologie en rapport avec le gene bcl-2 au moyen d'oligomeres antisens de bcl-2
WO2002057480A2 (fr) * 2001-01-22 2002-07-25 Genta Incorporated Methodes et compositions destinees a traiter un trouble associe a la proliferation cellulaire au moyen d'oligomeres leurres cre, d'oligomeres antisens bcl-2 et d'oligomeres hybrides correspondants

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Title
ELEZ ROBERT ET AL: "Tumor regression by combination antisense therapy against Plk1 and Bcl-2.", ONCOGENE, vol. 22, no. 1, 9 January 2003 (2003-01-09), pages 69 - 80, XP001181107, ISSN: 0950-9232 (ISSN print) *
GEARY R S ET AL: "ANTISENSE OLIGONUCLEOTIDE INHIBITORS FOR THE TREATMENT OF CANCER: 1. PHARMACOKINETIC PROPERTIES OF PHOSPHOROTHIOATE OLIGODEOXYNUCLEOTIDES", ANTI-CANCER DRUG DESIGN, BASINGSTOKE, GB, vol. 12, 1997, pages 383 - 393, XP009025247, ISSN: 0266-9536 *
HELLER R ET AL: "Phase I/II trial for the treatment of cutaneous and subcutaneous tumors using electrochemotherapy.", CANCER. UNITED STATES 1 MAR 1996, vol. 77, no. 5, 1 March 1996 (1996-03-01), pages 964 - 971, XP009029961, ISSN: 0008-543X *
PARK J W ET AL: "Tumor targeting using anti-her2 immunoliposomes", JOURNAL OF CONTROLLED RELEASE, ELSEVIER SCIENCE PUBLISHERS B.V. AMSTERDAM, NL, vol. 74, no. 1-3, 6 July 2001 (2001-07-06), pages 95 - 113, XP004297516, ISSN: 0168-3659 *
SPAENKUCH-SCHMITT BIRGIT ET AL: "Downregulation of human polo-like kinase activity by antisense oligonucleotides induces growth inhibition in cancer cells", ONCOGENE, vol. 21, no. 20, 9 May 2002 (2002-05-09), pages 3162 - 3171, XP001180957, ISSN: 0950-9232 *
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1546179A4 (fr) * 2002-07-30 2007-12-19 Isis Pharmaceuticals Inc Modulation antisens de l'expression de kinase de type polo
RU2413519C2 (ru) * 2005-05-17 2011-03-10 Чанчунь Хуапу Байотекнолоджи Ко., Лтд. Олигонуклеотиды или их функциональные гомологи, содержащая их композиция и способ лечения в-клеточной опухоли
US8133874B2 (en) 2005-05-17 2012-03-13 Changchun Huapu Biotechnology Co., Ltd. Oligonucleotide or its functional homologue, a composition comprising the same and a method of treating B cell neoplasm
US8450292B2 (en) 2005-05-17 2013-05-28 Changchun Huapu Biotechnology Co., Ltd. Oligonucleotides or their functional homologues, a composition comprising the same and a method of treating B cell neoplasm
WO2007089367A3 (fr) * 2005-12-27 2008-10-09 Genentech Inc Procedes d'utilisation d'antagonistes de kinase hedgehog permettant d'inhiber la signalisation hedgehog et de traiter les troubles dont la mediation est assuree par hedgehog
AU2006337085B2 (en) * 2005-12-27 2013-12-19 Curis, Inc. Methods of using hedgehog kinase antagonists to inhibit hedgehog signaling and to treat hedgehog mediated disorders
WO2021155073A1 (fr) * 2020-01-29 2021-08-05 Cardiff Oncology, Inc. Traitement de leucémies et de lymphomes avec des combinaisons d'inhibiteurs de bcl-2 et d'inhibiteurs de plk1

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DE10258677A1 (de) 2004-06-24

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