WO2004016810A2 - Utilisation de substances se liant a mrp4 pour diagnostiquer et traiter des maladies cancereuses - Google Patents

Utilisation de substances se liant a mrp4 pour diagnostiquer et traiter des maladies cancereuses Download PDF

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Publication number
WO2004016810A2
WO2004016810A2 PCT/DE2003/002159 DE0302159W WO2004016810A2 WO 2004016810 A2 WO2004016810 A2 WO 2004016810A2 DE 0302159 W DE0302159 W DE 0302159W WO 2004016810 A2 WO2004016810 A2 WO 2004016810A2
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WIPO (PCT)
Prior art keywords
mrp4
protein
substance
peptide
prostate
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Ceased
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PCT/DE2003/002159
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German (de)
English (en)
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WO2004016810A3 (fr
Inventor
Uta Schwidetzky
Christian Pilarsky
Bernd Hinzmann
Thomas Specht
André ROSENTHAL
Rosemarie Lichtner
Edgar Dahl
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Metagen Pharmaceuticals GmbH
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Metagen Pharmaceuticals GmbH
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Priority to AU2003250766A priority Critical patent/AU2003250766A1/en
Publication of WO2004016810A2 publication Critical patent/WO2004016810A2/fr
Publication of WO2004016810A3 publication Critical patent/WO2004016810A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4748—Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE

Definitions

  • the invention relates to new uses of Mrp4 or sequences derived therefrom for screening for substances which bind to it, and to the use of substances which bind to rp4 for the diagnosis and / or treatment of tumor diseases.
  • Mrp4 is part of the ATP binding cassette superfar ⁇ il of the transport proteins, which use the energy of the ⁇ TP hydrolysis for their activity. According to MA Barrand et al., Gen. Pharmacol. 28: 639-645 (1997), Mrp4 is associated with changes in drug accumulation and distribution.
  • the anti-viral agent PMEA the anti-cancer agents ⁇ -mecaptopurine, 6-thioguanine and estradiol 17- ⁇ -D-glucuronide
  • the transport of these agents through Efflux through the cell membrane by means of rp4 is known (K. Lee et al. , J Natl Cancer Inst 92: 1934-1940 (2000); ZS .
  • Mrp4 was detected in normal prostate tissue and in stably transfected NIH3T3 cells both in cytoplasm a and in the membrane (K. Lee et al., J Natl Cancer Inst 92: 1934-1940 (2000)). Mrp4 is predominantly expressed in normal prostate tissues and to a lesser extent in various other normal tissues. Expression is also to be observed in various tumor cell lines (P. Borst et al., J Natl Cancer Inst 92: 1295-1302 (2000)).
  • MDR Multi-Drug Resistance
  • the invention is based on the technical problem of specifying pharmaceutical compositions for diagnosing and / or treating prostate and / or bladder and / or ovarian cancer and means for identifying them.
  • the invention is based in particular on the technical problem of identifying and treating resistant tumors.
  • the invention teaches the use of a nucleic acid coding for Mrp4 and / or a Mrp4 peptide or protein for the detection of prostate and / or bladder and / or ovarian tumors or for the detection of a risk of Disease of prostate and / or bladder and / or ovary tumors, in particular tumors with increased resistance, with a prostate or bladder or ovary tissue sample, for example in vitro, for transcription of Mrp4 RNA or for overexpression of a Mrp4 protein is examined.
  • a nucleic acid coding for Mrp4 or a detector substance that binds to Mrp4 protein or peptide, preferably containing a reporter group, can be used for the detection, whereby binding of said nucleic acid and / or said protein or peptide to the detector substance is detected semi-quantitatively or quantitatively.
  • the invention further teaches the use of a Mrp4 RNA or a Mrp4 protein or peptide for screening for substances which bind to it, in particular prospective active substances for inhibiting said RNA or said protein or peptide or prospective detector substances, with a prospective substance or a mixture of such prospective substances with said RNA or said protein or peptide is contacted, binding events being ascertained using a binding assay, and a binding prospective substance being selected, if appropriate after deconvolution.
  • the invention teaches the use of a substance which inhibits or binds to Mrp4 for producing a pharmaceutical composition for the treatment of prostate and / or bladder and / or ovary tumors, in particular for the treatment of resistant tumors.
  • the substance can be an antibody which is obtained by immunizing a non-human mammal with a Mrp4 peptide or protein with cDNA coding therefor transfected cells, with tumor cells expressing such a peptide or protein endogenously, or with recombinantly produced Mrp4 peptides or proteins, or a phage display antibody.
  • the substance can also be a mimicry compound of an antibody against a Mrp4 peptide or protein.
  • the substance can be an aptamer, an antisense RNA, or a ribozyme.
  • the substance can additionally, in particular in the case of a bispecific antibody or a mimicry compound, carry a cytotoxic and / or immunostimulating component.
  • the pharmaceutical composition can be prepared for local application in tissue containing tumor cells.
  • the invention can be used in a process for
  • a detector substance in one embodiment being applied with a reporter group to the tissue to be examined, possibly in vitro after tissue removal, the tissue to be examined then being subjected to a detection method step is which is sensitive to the reporter group, and in the case of detection of a defined minimum value of the reporter group in the tissue the tissue is qualified as, possibly resistant, containing tumor cells, and one
  • a pharmaceutical composition according to the invention is administered to a patient in a physiologically effective dose, optionally with, before or after, a different, conventional anti-cancer Active ingredient is presented in the same or different dosage forms.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least two components A and B, component A being a substance according to one of claims 4 to 8, component B being a (customary) anti-cancer active ingredient, components A and B being prepared alternatively can be i) as spatially separate components of a multicomponent preparation, intended for simultaneous or successive administration and galenically prepared as identical or different administration forms, or ii) as a combination preparation in the form of a spatially connected and uniform administration form.
  • the invention is based on the knowledge that Mrp4 is overexpressed in prostate and bladder and / or ovary tumors, ie the expression in said tumor tissues is higher compared to normal cells of the same tissue, and the technical teaching that can be derived therefrom that Mrp4 can be used as a target molecule in the diagnosis and therapy of these diseases, in particular in the case of intrinsic resistance or acquired or acquired resistance. Mrp4 can thus serve as a marker for the identification of tumor cells, in particular resistant tumor cells, in the said tumor tissues.
  • the inhibition of Mrp4 offers the possibility of overcoming resistances or not even allowing them to occur, especially in conjunction with conventional chemotherapy agents. In this respect, the invention can also be used to prevent the development of resistance. Because by preventing the efflux of chemotherapeutic agents given due to Inhibition of Mrp4 ensures the long-term effect of these chemotherapeutic agents in all target cells.
  • Mrp4 has substrate specificity, for example to cyclic nucleotides, purine analogs and nucleoside-based antivirals; obtaining the expression pattern for Mrp4 can therefore facilitate the selection of potentially suitable active substances or the exclusion of potentially unsuitable active substances or chemotherapeutic agents.
  • a detector substance according to the invention can be used for diagnosis in vivo to test for Mrp4 phenotype. If an overexpression of Mrp4 compared to normal tissue of the same type is found, the use of the pharmaceutical composition according to the invention is indicated.
  • the invention can be used particularly advantageously in the case of androgen-sensitive tumors or tumor cells.
  • the substance which binds to Mrp4 additionally carries a cytotoxic and / or immunostimulating component. This ultimately leads to the fact that almost exclusively tumor cells are killed, either by the cytotoxicity or by the attack by the stimulates the immune system, while normal cells are practically completely preserved in the tissue. If a cytotoxic component is used, it will be particularly recommended if the pharmaceutical composition is prepared for local application in tissue containing tumor cells, for example for injection.
  • the invention further relates to a Mrp4 protein or peptide containing a partial sequence of at least 4 amino acids from SEQ ID 10, in particular from SEQ ID 11, or containing SEQ ID 10, in particular SEQ ID 11. or consisting of such a sequence, but not a protein or peptide according to or encoded by Genbank AccNo NM_005845, AY_081219 and XM_036453.
  • the invention relates to a nucleic acid coding for such a protein or peptide, in particular a sequence according to SEQ ID 9 or a partial sequence thereof.
  • a protein or peptide according to the invention or a nucleic acid coding therefor can be used in all the contexts described above and below.
  • Mrp4 Genbank AccNo NM_005845, AY__081219 and XM_036453.
  • Mrp4 is used for all human isoforms, known or new, based on nucleic acids or amino acids. These terms also include those in the context of these terms
  • nucleic acid sequences for example immunization sequences. Also included are homologs, the Homology is at least 80%, preferably more than 90%, most preferably more than 95%. In the case of the nucleic acid sequences, complementary or allelic variants are also included.
  • sequences are included which only represent partial sequences of the explicitly disclosed sequences, for example one exon or several exons, or sequences complementary thereto, with the proviso that, in the case of the nucleic acids, these partial sequences are of sufficient length for hybridization with a nucleic acid according to the invention, have at least 30 to 50 bases and, in the case of proteins or peptides, bind to a protein- or peptide-specific target molecule with at least the same affinity.
  • all nucleic acids hybridizing with nucleic acids according to the invention are included, namely those which are under stringent conditions (5 ° C. to 25 ° C.
  • the invention also includes expression cassettes, ie one or more of the nucleic acid sequences according to the invention with at least one control or regulatory sequence.
  • Such an expression cassette can also comprise a sequence for a known protein, a fusion protein being formed in the course of the translation from a known protein and a protein or peptide according to the invention. Antisense sequences to the above nucleic acid sequences are also included.
  • RNA and correlating DNA and vice versa are included, as are genomic DNA and correlated cDNA and vice versa and RNAi.
  • the terms of Mrp4 nucleic acids or protein or peptides also include partial sequences in addition to the full lengths of the sequences mentioned (see also the preceding paragraph), with a minimum length of 12 to 30 nucleotides, for example 30 to 90 nucleotides, in the case of nucleic acids and a minimum length of 4 to 10 amino acids, for example 10 to 30 amino acids, in the case of peptides or proteins.
  • treatment also includes prophylaxis.
  • An inhibitor is a compound or substance which either inhibits the formation of Mrp4 or reduces the activity of Mrp4 formed, based on the Mrp4 activity in the absence of the inhibitor.
  • an inhibitor can be a substance that interferes with the cascade of Mrp4.
  • an inhibitor can be a substance that binds with Mrp4 formed, in such a way that further physiological interactions with endogenous substances are at least reduced.
  • Mimicry molecules are compounds that simulate the variable region, in particular the binding region of an antibody, and bind to a target molecule in the same place as the underlying antibody.
  • antibody includes polyclonal antibodies, monoclonal antibodies, non-human, human and humanized antibodies, anti-idiotypic antibodies and phage display antibodies, but also chimeric antibodies as well specific fragments of the light and / or the heavy chain of the variable region of the underlying antibodies of the above type.
  • the production or production of such antibodies with predetermined immunogens is well known to the average person skilled in the art and need not be explained in more detail.
  • the term antibody also includes bispecific antibodies. Bispecific antibodies combine a defined immune cell activity with a specific tumor cell recognition, whereby tumor cells are killed. A bispecific antibody binds on the one hand to a trigger molecule of the immune effector cell (eg CD3, CD16, CD64) and on the other hand to antigens of the tumor target cell.
  • a trigger molecule of the immune effector cell eg CD3, CD16, CD64
  • Counter ions for ionic compounds are, for example, Na + , K + , Li + or cyclohexylammonium.
  • Suitable solid or liquid pharmaceutical preparation forms are, for example, granules, powders, dragees, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions (IV, IP, IM) as well as preparations with a protracted active ingredient -Release, in the production of which conventional auxiliaries such as carriers, explosives, binders, coatings, swelling agents, lubricants or lubricants, flavoring agents, sweeteners and solubilizers are used.
  • auxiliaries such as carriers, explosives, binders, coatings, swelling agents, lubricants or lubricants, flavoring agents, sweeteners and solubilizers are used.
  • a pharmaceutical composition according to the invention can be produced by mixing at least one Mrp4 inhibitor used according to the invention in a defined dose with a pharmaceutically suitable and physiologically compatible carrier and, if appropriate, other suitable active ingredients, additives or auxiliaries with a defined inhibitor dose and preparing the desired dosage form.
  • Tumor cells overexpress Mrp4 specifically or differentially if Mrp4 is expressed in at least 10% higher amounts than normal cells of the same tissue.
  • Cytotoxic components or groups are compounds which directly or indirectly induce apoptosis or lead to necrosis or at least inhibit growth. In addition to being coupled to a substance according to the invention, these can also be used as component B. In addition to radioisotopes (for example 188Re, 213Bi, 99mTc, 90Y, 131J, 177Lu), such groups or compounds can in particular be cytostatic agents which are used in tumor therapy.
  • radioisotopes for example 188Re, 213Bi, 99mTc, 90Y, 131J, 177Lu
  • such groups or compounds can in particular be cytostatic agents which are used in tumor therapy.
  • alkylating agents for example mechlorethamine, ifosfamide, chlorambucil, cyclophosphamide, melphalan, alkylsulfonates, busulphan, nitrosoureas, carmustine, lomustine, semustin, triazenes, dacarbazine
  • antitamabolites for example folic acid antagonists, methotrexate, fluorimidiloxane, fluorimidine
  • mitosis inhibitors e.g.
  • vinca alkaloids voncristine, vinblastine, paclitaxal, docetaxel, protaxel
  • epipodophyllotoxins e.g. etoposide, teniposide
  • antibiotics e.g. Dactinomycin, daunorubicin, idarubicin, anthracycline, bleomycin, L-asparaginase
  • platinum complex compounds e.g. cisplatin
  • hormones and related compounds e.g. adrenal cortex steroids, aminogluthetimide, gestagens, estrogens, androgens, anti-estrogens, tamoxifen, tamoxifen).
  • the coupling takes place in such a way that the affinity for Mrp4 is reduced by not more than 90%, preferably 50%, based on the substance without a cytostatic group, and the cytostatic effect of the group is not reduced by more than 90%, preferably 50%, based on the compound without substance.
  • An immunostimulating component is usually a protein or an effective component thereof, which stimulates cells of the immune system.
  • cytokines such as M-CSF, GM-CSF, G-CSF, interferons such as IFN-alpha, -beta, -gamma, interleukins such as IL-1 to -16 (except -8), human LIF, Che okines such as Rantes, MCAF, MIP-1-alpha, -beta, NAP-1 and IL-8.
  • This component can also be used as a component B.
  • a reporter group is an atom, molecule or a compound which, in conjunction with an assay placed thereon, enables the detection of the reporter group and the compound or substance thus connected to the reporter group.
  • reporter groups and associated detection methods are: 32P labeling and intensity measurement using phosphoimager. Many more. Examples are known to the person skilled in the art and do not need to be listed in detail.
  • a substance that binds to Mrp4 can be a substance that binds a Mrp4 protein or a Mrp4 RNA.
  • Resistance refers to the resistance of malignant cells to chemotherapy drugs.
  • a cell is in the
  • a cell is resistant if the time to cell death is prolonged or the proliferation rate is increased compared to a non-resistant reference cell of different cell types and the same dosage.
  • Definitions expanded in the context of the above definition in relation to the narrow sense of the word also include the specific terms in the narrow sense of the word.
  • Example 2 Overexpression in prostate tumor Paired prostate tumor and normal tissues were removed by laser microdissection from 54 patients. The RNA prepared from it was amplified, labeled with digoxygenin and hybridized on a DNA chip using Affymetrix technology. The results of the analysis of the chip are shown in FIG. 1. It can be seen that in 55% of the prostate tumors (28 out of 54 patients) the expression is increased by at least a factor of 2.
  • Example 3 Overexpression in prostate and ovarian tumor.
  • FIG. 2 shows results of the expression of Mrp4 on prostate and bladder tumors and the associated normal tissues, obtained as stated above, from a cancer profiling array.
  • the Mrp4 sequence was labeled with 32P-dCTP using random hexamer priming and hybridized to the cancer profiling array. This contains 225 cDNA pairs, each pair representing tumor and normal tissue from one patient. It can be seen that Mrp4 is overexpressed in several prostate and ovarian tumors.
  • Example 4 Overexpression in prostate tumor.
  • Mrp4-specific oligonucleotide primers were generated and used for quantitative PCR (TaqMan), the first strand of cDNA coming from different tissues and cell lines, as indicated in FIG. 3. Mann first recognizes that there is significant overexpression of Mrp4 (4-9-fold) in 5 out of 15 prostate tissue pairs. No expression takes place in other normal tissues of FIG. 3. The same applies to the cell lines examined, with the exception of the androgen-sensitive tumor cell line LNCaP.
  • FIG. 4 A detailed representation of the investigations on cell lines is given in FIG. 4, with the strong expression in the prostate tumor cell line LNCaP first becoming more apparent. However, it can also be seen that expression in non-androgen-sensitive cell lines, such as, for example, PC-3 and DU-145, is comparatively low.
  • an anti-Mrp4 antibody is labeled with a marker molecule (e.g. radioisotope).
  • a marker molecule e.g. radioisotope
  • 3 10 6 Mrp4-transfected human cells or tumor cells with high endogenous Mrp4 expression, for example LNCaP cells are transplanted. After a period of time sufficient to develop metastases to a secondary site in the body, for example 30 days after the transplant, the mice become infected with labeled antibodies.
  • the control animals are treated with an irrelevant antibody. A few hours after the antibody application, the animals are sacrificed and tissue sections are made from all organs. These sections are examined for the presence of labeled anti-Mrp4 antibody.
  • the anti-Mrp4 antibodies are polyclonal antibodies against human Mrp4 protein conjugated to a carrier protein, raised in rabbits and affinity-purified with the specific immobilized peptides.
  • immunization peptides are given in Figure 6 (SEQ ID 1 to 4).
  • Cells transfected with Mrp4 cDNA, or partial sequences thereof, such as, for example, COS cells or NIH3T3 cells, can also be used as immunogens.
  • Tumor cells expressing Mrp4 endogenously are also suitable.
  • recombinantly produced Mrp4 or partial sequences thereof, which are expressed in producer cells such as E. coli or insect cells can also be used for the immunization.
  • Example 6 Immunohistochemical detection of tumor cells.
  • FIG. 5 shows various hammerhead ribozymes which cut Mrp4 at the points shown and thus inhibit or at least reduce the activity of any translation products.
  • Suitable antisense RNA sequences are, for example, 5'-UCACCUCCUGGUACACGGGCAG-3 '(Seq. ID 7) and 5'-GCAGAUGUUCGCGUCCUGCAGC-3 "(Seq. ID 8). It is also possible to construct primers by means of which RNAi probes are generated to inhibit Mrp4 by gene silencing (RNA interaction).

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Abstract

La présente invention concerne des utilisations de Mrp4 pour diagnostiquer et traiter des tumeurs de la prostate et/ou de la vessie et/ou des ovaires et pour cribler des substances correspondantes.
PCT/DE2003/002159 2002-07-26 2003-06-23 Utilisation de substances se liant a mrp4 pour diagnostiquer et traiter des maladies cancereuses Ceased WO2004016810A2 (fr)

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AU2003250766A AU2003250766A1 (en) 2002-07-26 2003-06-23 Use of an mrp4 binding substances for the diagnosis and treatment of cancer

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DE10234901.0 2002-07-26
DE2002134901 DE10234901A1 (de) 2002-07-26 2002-07-26 Verwendung von am Mrp4 bindenden Substanzen zur Diagnose und Behandlung von Krebserkrankungen

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WO2004016810A3 WO2004016810A3 (fr) 2004-11-11

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005001092A3 (fr) * 2003-05-20 2006-06-29 Wyeth Corp Compositions et procedes pour diagnostiquer et traiter le cancer
EP1784511A4 (fr) * 2004-08-13 2009-03-11 Millennium Pharm Inc Genes, compositions, kits, et methodes pour identification, evaluation, prevention et therapie du cancer de la prostate

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SG185027A1 (en) * 2010-05-03 2012-11-29 Genentech Inc Compositions and methods for the diagnosis and treatment of tumor

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6759238B1 (en) * 1999-03-31 2004-07-06 St. Jude Children's Research Hospital Multidrug resistance associated proteins and uses thereof
CA2397741A1 (fr) * 2000-01-14 2001-07-19 Corixa Corporation Compositions et methodes destinees au traitement et au diagnostique du cancer de la prostate
EP1474528A4 (fr) * 2000-10-13 2006-06-14 Protein Design Labs Inc Procedes de diagnostic du cancer de la prostate, compositions et procedes de criblage de modulateurs du cancer de la prostate
EP1217066A1 (fr) * 2000-12-21 2002-06-26 Universiteit Gent Modulation de l'activité de transport d'une cassette de liaison d'ATP
CA2432991A1 (fr) * 2001-01-23 2002-08-01 Irm, Llc Genes surexprimes dans des maladies de la prostate servant de cibles diagnostiques et therapeutiques
WO2003009814A2 (fr) * 2001-07-25 2003-02-06 Millennium Pharmaceuticals, Inc. Nouveaux genes, compositions, trousses et methodes d'identification, evaluation, prevention, et traitement du cancer de la prostate

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005001092A3 (fr) * 2003-05-20 2006-06-29 Wyeth Corp Compositions et procedes pour diagnostiquer et traiter le cancer
EP1784511A4 (fr) * 2004-08-13 2009-03-11 Millennium Pharm Inc Genes, compositions, kits, et methodes pour identification, evaluation, prevention et therapie du cancer de la prostate

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AU2003250766A1 (en) 2004-03-03
WO2004016810A3 (fr) 2004-11-11

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