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US20030186906A1 - Mixture comprising an inhibitor or suppresor of a gene and a molecule binding to an expression product of that gene - Google Patents

Mixture comprising an inhibitor or suppresor of a gene and a molecule binding to an expression product of that gene Download PDF

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US20030186906A1
US20030186906A1 US10/220,033 US22003302A US2003186906A1 US 20030186906 A1 US20030186906 A1 US 20030186906A1 US 22003302 A US22003302 A US 22003302A US 2003186906 A1 US2003186906 A1 US 2003186906A1
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gene
mixture
molecule
expression
binding
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Karl-Hermann Schlingensiepen
Reimar Schlingensiepen
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Biognostik Gesellschaft fuer Biomolekulare Diagnostik mbH
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Biognostik Gesellschaft fuer Biomolekulare Diagnostik mbH
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Assigned to BIOGNOSTIK GESELLSCHAFT FUR BIOMOLEKULARE DIAGNOSTIK MBH reassignment BIOGNOSTIK GESELLSCHAFT FUR BIOMOLEKULARE DIAGNOSTIK MBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SCHLINGENSIEPEN, KARL-HERMANN, SCHLINGENSIEPEN, REIMAR
Publication of US20030186906A1 publication Critical patent/US20030186906A1/en
Priority to US12/382,415 priority Critical patent/US8703729B2/en
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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
    • C12N15/1136—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 growth factors, growth regulators, cytokines, lymphokines or hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • 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
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • 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
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • 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

  • Binding can also be achieved by nucleic acid derivatives like aptamers and spiegelmers.
  • the invention pertains to a mixture comprising at least one inhibitor or suppressor of the expression of a gene and at least one molecule binding to an expression product of said gene.
  • the at least one molecule preferably inhibits the functional activity of the expression product.
  • U.S. Pat. No. 5,891,858 discloses antisense polynucleotides to human transforming growth factor alpha (TGF- ⁇ ) and the receptor for human epidermal growth factor (rEGF). It discloses the combination of an antisense polynucleotide for rEGF with antibodies to rEGF (anti-rEGF) but the anti-rEGF is not able to inhibit the activity of the EGF-receptor. In contrast anti-rEGF is a stimulator of the receptor.
  • the at least one inhibitor or suppressor is an nucleic acid molecule or derivative thereof.
  • the at least one nucleic acid molecule is preferably an oligonucleotide, an antisense oligonucleotide and/or a ribozyme inhibiting or interfering with the expression of a gene which plays a role in a patho-physiological event.
  • the DNA delivery system comprises viral or non-viral vectors or both and additionally anionic lipids, cationic lipids, non-cationic lipids or mixtures thereof.
  • the antisense and/or ribozyme molecule can also be modified by coupling it to an enhancer of uptake and/or inhibitory activity.
  • the nucleic acid molecules are coupled to or mixed with folic acid, hormones, steroid hormones such as oestrogene, progesterone, corticosteroids, mineral corticoids, peptides, proteoglycans, glycolipids, phospholipids and derivatives thereof.
  • hormones such as oestrogene, progesterone, corticosteroids, mineral corticoids, peptides, proteoglycans, glycolipids, phospholipids and derivatives thereof.
  • nucleic acid sequences are known to those skilled in the art. More sequences and methods for selecting such sequences can be found for example in WO 94/25588 or WO 98/33904.
  • the inhibitor or supressor is a peptide, protein and/or low molecular weight substance, which is able to bind to DNA or RNA coding for the gene, thus inhibiting or suppressing expression of the gene.
  • Suitable proteins also comprise antibodies and antibody fragments.
  • the mixture of the invention comprises preferably as the at least one molecule binding to the expression product of the gene an antibody, antibody fragment, such as a F ab fragment, single chain antibody or combinations thereof.
  • the antibody, antibody fragment, such as a F ab fragment, single chain antibody or combinations thereof are e.g. obtainable by screening of antibody libraries and testing the expression products for binding to an expression product of the gene.
  • the at least one molecule binding to an expression product of the gene is preferably a peptide and/or protein.
  • the peptide and/or protein is e.g. obtainable by screening an expression library and testing the expression products for binding to an expression product of the gene.
  • the synthetic peptide and/or protein may also be obtained by screening randomly synthesised peptides and/or polypeptides for binding to an expression product of the gene. Peptides binding to expression products are for example disclosed in EMBO J. 20(2001) 340-349. The peptides bind to MIA (Melanoma Inhibitory Activity), thus inhibiting the functional activity of MIA. Suitable peptides (SEQ ID No. 18-41) are for example
  • the mixture of the invention comprises a low molecular weight molecule binding to an expression product of the gene.
  • the low molecular weight molecule is obtainable by using combinatorial chemistry and testing the products for binding to an expression product of the gene.
  • Low molecular weight molecules as used herein are molecules having up to 100 carbon atoms in combination with further atoms such as N, S, O, P and the like. Suitable compounds binding to an expression product can be found in FIG. 2, all binding to MIA.
  • the molecule or factor binding to an expression product of the gene may also be DNA or RNA molecule or a derivative thereof including aptamers and/or aptamers and/or aptamers that bind to the expression product to the gene.
  • the gene is selected from the group consisting of TGF- ⁇ , erbB-2, MIA, c-jun, junB, c-fos, VCAM, NF-kappaB p65, NF-kappa B p50, ICAM, VEGF and NF-kB 2.
  • the invention pertains as well to oligonucleotides having the sequences Seq. ID. No 1 to 17.
  • a medicament comprising the mixture of the invention is also subject matter of the present invention.
  • the invention further concerns a method of using a mixture comprising at least one suppressor or inhibitor of the expression of a gene and at least one molecule or factor binding to an expression product of said gene for treating tumors, immune disorders, or improving organ or cell transplantation, including transplantation of hematoietic stem cells and their derivatives including erythrocytes, white blood cells, platelets, thrombocytes and their precursor cells.
  • Organ transplantation includes transplantation of liver, kidney, heart, lung, gastrointestinal organs, bone, pancreas, cartilage, neurones, islet cells and stem cells from which these organs can be derived or reconstructed.
  • the mixture of the present invention is also useful in Drug Target Validation, i.e. to identify genes that are relevant for a certain pathological state by testing the effect of the mixture of the present invention on a cell system or organism.
  • the invention is directed to a method for reducing a functional activity of a gene product in a biological system comprising treatment of the biological system simultaneously or successively with at least one inhibitor or suppressor of the expression of a gene and at least one molecule inhibiting functional activity of an expression product of said gene.
  • the biological system may be a cell, a cell culture, an organ or an organism.
  • FIG. 1 shows a strongly supra-additive effect of a combination of both the blocking of a gene with an antisense molecule combined with a neutralising antibody.
  • PBMC Peripheral blood mononuclear cells
  • glioma tumor cells were harvested, washed twice in 5% FCS/PBS solution and resuspended at 10 Mio cells/ml in 5% FCS/PBS. Calcein-AM (Molecular Probes, USA) was added to a final concentration of 25 ⁇ M. The cells were labelled for 30 min at 37° C. then washed twice in 5% FCS/PBS, adjusted to 1 Mio cells/ml and loaded into 96-well U-shaped microtiter plates at the final concentration of 0.1 Mio/100 ⁇ L/1 well (Nunc, Denmark).
  • antisense phosphorothioate TGF- ⁇ 2 oligonucleotides (f.c. 2-5 ⁇ M)
  • Hematopoietic Stem cells were collected by apheresis after mobilisation from bone marrow with a daily dose of 10 ⁇ g/kg/day of rhG-CSF for 5 days or from cord blood (cord blood stem cells) and enrichment of CD34+ cells achieved with immunopurification.
  • the multipotent progenitor fraction of both, bone marrow derived and cord blood derived stem cells are of critical relevance for clinical application.
  • a problem of current stem cell transplantation is the low number of stem cells generated by optimised cytokine cocktails.
  • a critical problem for long term success is the quiescence and maturation of multipotent progenitor fraction by current treatment with cytokine cocktails.
  • Both the number of cells and the proliferative capacity of bone marrow stem cells can be improved by treatment with TGF- ⁇ 1 inactivating antibodies or with TGF- ⁇ 1 antisense oligonucleotides.
  • TGF- ⁇ 1 inactivating antibodies had a strongly supra-additive effect.
  • Bone marrow derived and cord blood derived stem cells were treated with either
  • the number of multipotent proliferating progenitor cells was increased by 85% through treatment with TGF- ⁇ 1 antisense oligonucleotides compared to controls.
  • the number of multipotent proliferating progenitor cells was increased by more than 350% through treatment with a combination of both, TGF- ⁇ 1 inactivating antibodies and TGF- ⁇ 1 antisense oligonucleotides compared to controls.
  • TGF- ⁇ 1 binding peptide and TGF- ⁇ 1 antisense oligonucleotides had a similarly strongly supra-additive effect on the proliferation of multipotent proliferating hematopoietic progenitor cells.
  • the number of multipotent proliferating progenitor cells was increased by 85% through treatment with TGF- ⁇ 1 antisense oligonucleotides compared to controls.
  • the number of multipotent proliferating progenitor cells was increased by more than 3-fold through treatment with a combination of both, TGF- ⁇ 1 binding peptide and TGF- ⁇ 1 antisense oligonucleotides compared to controls.
  • Inhibition of tumor cell proliferation was between 18% and 31% with antisense c-erbB-2 oligonucleotides, between 13 and 34% with antibodies, but by more than 85% with a combination of the two.
  • MIA-secreting melanoma reduced their migration activity, as well as increasing their adhesion to matrices, both suggesting a strong inhibitory effect of MIA inhibitors and tumor invasion and metastasis.
  • Supra-additive inhibition can also be achieved by combining a transcription factor or its binding domain, binding to a regulatory sequence of receptors, enzymes, transcription factors, cell adhesion molecules, cytokines or growth factors, such as TGF- ⁇ , MIA, VCAM, ICAM, c-jun, junB, NF-kappaB, VEGF or integrins genes with a molecule of small molecular weight, e.g. derived by combinatorial chemistry, binding to receptors, enzymes, transcription factors, cell adhesion molecules, cytokines or growth factors, such as TGF- ⁇ , MIA, VCAM, ICAM, c-jun, junB, NF-kappaB, VEGF or integrins.
  • a regulatory sequence of receptors such as TGF- ⁇ , MIA, VCAM, ICAM, c-jun, junB, NF-kappaB, VEGF or integrins.
  • Supra-additive inhibition can also be achieved by combining a peptide or a protein, binding to the mRNAs transcribed from receptors, enzymes, transcription factors, cell adhesion molecules, cytokines, or growth factors, such as TGF- ⁇ , MIA, VCAM, ICAM, c-jun, junB, NF-kappaB, VEGF or integrin genes with a small molecule binding to receptors, enzymes, transcription factors, cell adhesion molecules, cytokines, or growth factors, such as TGF- ⁇ , MIA, VCAM, ICAM, c-jun, junB, NF-kappaB, VEGF or integrins.
  • Supra-additive inhibition can also be achieved by combining peptide, a protein e.g. a transcription factor or its binding domain, binding to a regulatory sequence of receptors, enzymes, transcription factors, cell adhesion molecules, cytokines growth factors, such as TGF- ⁇ , MIA, VCAM, ICAM, c-jun, junB, NF-kappaB, VEGF or integrin genes with a Spiegelmer binding to receptors, enzymes, transcription factors, cell adhesion molecules, cytokines growth factors, such as TGF- ⁇ , MIA, VCAM, ICAM, c-jun, junB, NF-kappaB, VEGF or integrins.
  • a protein e.g. a transcription factor or its binding domain
  • cytokines growth factors such as TGF- ⁇ , MIA, VCAM, ICAM, c-jun, junB, NF-kappaB, VEGF or integrins.
  • Supra-additive inhibition can also be achieved by combining a transcription factor or its binding domain, binding to a regulatory sequence of receptors, enzymes, transcription factors, cell adhesion molecules, cytokines or growth factors, such as TGF- ⁇ , MIA, VCAM, ICAM, c-jun, junB, NF-kappaB, VEGF or integrin genes with peptides binding to receptors, enzymes, transcription factors, cell adhesion molecules, cytokines or growth factors, such as TGF- ⁇ , MIA, VCAM, ICAM, c-jun, junB, NF-kappaB, VEGF or integrins.
  • a transcription factor or its binding domain binding to a regulatory sequence of receptors, enzymes, transcription factors, cell adhesion molecules, cytokines or growth factors, such as TGF- ⁇ , MIA, VCAM, ICAM, c-jun, junB, NF-kappaB, VEGF or integrins.
  • Supra-additive effects can also be achieved by combining an inbibitor of c-jun expression with a molecule binding the c-jun gene product or derivative thereof. Such mixtures are useful for the protection of neurones to ischaemia, hypoxia, degeneration or overstimulation.
  • the HPP-Q-assay compares cells cultivated in a control medium induding cytokines (IL-3, IL-6, IL-11, G-CSF, GM-CSF, SCF and Epo) with cells cultured in the same cytokine-containing medium in the presence of anti-TGF- ⁇ 1-blocking antibody.
  • the control reveals cytokine-responsive progenitors, while the addition of blocking TGF- ⁇ -antibody induces quiescent progenitors.
  • Table 1 shows that antisense TGF- ⁇ 1 increases the effect of the anti-TGF- ⁇ 1 antibody (TGF- ⁇ 1 AB) on CD34-positive cells from a lymphoma patient more than twofold, i.e. in the presence of antisense TGF- ⁇ 1 the cell number more than doubles compared to antibody alone.
  • Table 2 shows that also antibody amplifies the effect of antisense TGF- ⁇ 1 on CD34-positive cells from two lymphoma and one myeloma patient: The cell number gained with antisense-TGF- ⁇ 1 alone increases almost threefold if TGF- ⁇ 1 antibody is added as well.
  • Antisense-TGF- ⁇ 1 Antisense-TGF- ⁇ 1+TGF- ⁇ 1 AB Lymphoma 1 19,00 ⁇ 1,41 37,00 ⁇ 6,48 Lymphoma 2 24,00 ⁇ 2,34 63,33 ⁇ 5,31 Myeloma 23,33 ⁇ 5,13 60,00 + 3.45

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030162190A1 (en) * 2001-11-15 2003-08-28 Gorenstein David G. Phosphoromonothioate and phosphorodithioate oligonucleotide aptamer chip for functional proteomics
US20040242521A1 (en) * 1999-10-25 2004-12-02 Board Of Regents, The University Of Texas System Thio-siRNA aptamers
US20040265912A1 (en) * 2003-05-23 2004-12-30 Board Of Regents, The University Of Texas System Structure based and combinatorially selected oligonucleoside phosphorothioate and phosphorodithioate aptamer targeting AP-1 transcription factors
US20050118611A1 (en) * 2003-07-24 2005-06-02 Board Of Regents, The University Of Texas System Thioaptamers enable discovery of physiological pathways and new therapeutic strategies
US20050123939A1 (en) * 2002-10-16 2005-06-09 Board Of Regents, The University Of Texas System Bead bound combinatorial oligonucleoside phosphorothioate and phosphorodithioate aptamer libraries
US20050214772A1 (en) * 1998-10-26 2005-09-29 Board Of Regents, The University Of Texas System Thio modified aptamer synthetic methods and compositions
US20050239134A1 (en) * 2004-04-21 2005-10-27 Board Of Regents, The University Of Texas System Combinatorial selection of phosphorothioate single-stranded DNA aptamers for TGF-beta-1 protein
US20060121489A1 (en) * 2003-05-23 2006-06-08 Board Of Regents, The University Of Texas System High throughput screening of aptamer libraries for specific binding to proteins on viruses and other pathogens
US20060172925A1 (en) * 1998-10-26 2006-08-03 Board Of Regents, The University Of Texas System Thio-siRNA aptamers
US20080268423A1 (en) * 2002-08-16 2008-10-30 Alan Barrett Compositions and Methods Related to Flavivirus Envelope Protein Domain III Antigens
US20110223127A1 (en) * 2007-08-06 2011-09-15 Noxxon Pharma Ag SDF-1 Binding Nucleic Acids And The Use Thereof
US9035038B2 (en) 2006-07-18 2015-05-19 Noxxon Pharma Ag SDF-1 binding nucleic acids
US9758786B2 (en) 2016-02-09 2017-09-12 Autotelic, Llc Compositions and methods for treating pancreatic cancer
WO2024254199A1 (fr) * 2023-06-05 2024-12-12 Gmp Biotechnology Limited Agents tgfb2 anticancéreux à agents immunothérapeutiques

Families Citing this family (11)

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WO2024254199A1 (fr) * 2023-06-05 2024-12-12 Gmp Biotechnology Limited Agents tgfb2 anticancéreux à agents immunothérapeutiques

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ATE304858T1 (de) 2005-10-15
HK1049796A1 (en) 2003-05-30
EP1133988A1 (fr) 2001-09-19
AU2001260109A1 (en) 2001-09-24
EP1263446B1 (fr) 2005-09-21
WO2001068146A2 (fr) 2001-09-20
JP2003526684A (ja) 2003-09-09
JP4843177B2 (ja) 2011-12-21
US8703729B2 (en) 2014-04-22
EP1263446A2 (fr) 2002-12-11
HK1049796B (zh) 2006-01-20
DE60113511D1 (de) 2006-02-02

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