WO2003013485A1 - Inhibiteurs des recepteurs de hb-egf (erbb) pour traiter le myelome - Google Patents
Inhibiteurs des recepteurs de hb-egf (erbb) pour traiter le myelome Download PDFInfo
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- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
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- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
- A61K38/179—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
- A61K38/204—IL-6
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- A61K38/00—Medicinal preparations containing peptides
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P5/00—Drugs for disorders of the endocrine system
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- 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
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- 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
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
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- 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
Definitions
- the present invention relates to the treatment of multiple myeloma. It relates more particularly to the use of at least one inhibitor of epidermal growth factor (EGF) binding heparin (HB) or of at least one inhibitor of HB-EGF receptors, or ErbB receptors or of at least an inhibitor of associated transduction pathways for the preparation of medicaments useful for inducing apoptosis and / or inhibiting the proliferation of IL-6 dependent plasma tumor cells.
- EGF epidermal growth factor
- HB heparin
- ErbB receptors ErbB receptors
- the present invention also relates to the use of at least one inhibitor of the epidermal growth factor binding heparin HB-EGF or of at least one inhibitor of HB-EGF receptors, or ErbB receptors or of at least one inhibitor of associated transduction pathways in combination with at least one IL-6 inhibitor or at least one IL-6 receptor inhibitor or at least one inhibitor of associated transduction pathways for the preparation of medicaments useful for inducing apoptosis and / or inhibit proliferation of IL-6 dependent plasma tumor cells.
- Interleukin 6 (IL-6) and the other cytokines of the IL-6 family are important growth factors for malignant plasmocyte cells involved in multiple myeloma 0> 2 ). It is also known that IL-6 is mainly produced by cells in the environment of the bone marrow ( 2 > 3 ) and that the production of IL-6 by these cells is induced after interaction with myeloma cells.
- HB-EGF heparin-binding epidermal growth factor
- HB-EGF is a factor produced either in soluble form or in the form of transmembrane protein (6> 7 ).
- the membrane form is the diphtheria toxin receptor.
- HB-EGF is a ligand for epidermal growth factor receptors (ErbB1 and ErbB4) (6> 7 ). It is produced by various tumor cells and acts as an autocrine tumor growth factor (6> 7 ).
- the inhibitors of factor HB-EGF which are suitable for the purposes of the invention are all substances capable of inhibiting the proliferation or of inducing apoptosis of tumor plasmocyte cells, for example under the conditions defined in the illustrative examples below.
- substances capable of inhibiting the HB-EGF factor include, in particular, heparins, in particular low molecular weight heparin, diphtheria toxin and anti-HB-EGF antibodies, in particular antibodies anti-HB-EGF monoclonals, such as those described in the illustrative examples below.
- the inhibitors of the HB-EGF receptor which are suitable for the purposes of the invention are all substances capable of inhibiting the proliferation or of inducing apoptosis of tumor plasma cells, for example under the conditions defined in the examples below.
- suitable ErbB receptor inhibitors are in particular monoclonal anti-ErbB1 antibodies, such as for example the LA-1 monoclonal antibody, marketed by UBI (Lake Placid NY USA).
- the inhibitors of IL-6 which can be used for the purposes of the invention are, for example, corticosteroids, mutated IL-6 or other inhibitors of IL-6 and anti-IL-6 monoclonal antibodies, such as that in particular those directed against the gp 80 chain or the gp 130 chain, for example the monoclonal antibodies B-E8, produced by the company Diaclone (Besançon) and the IL-6 receptor inhibitors such as the monoclonal antibody B-R3, anti-transducer antibody to IL-6 gp 130, property of PINSERM and Diaclone, produced by Diaclone.
- an effective dose of each of the inhibitors used according to the invention must be used according to pharmacologically equivalent doses, deduced from the experimental data.
- the effective dose depends, of course, on the state of evolution of the myeloma, on the age, on the biological profile, on the clinical state of the patient and on other pharmacological parameters dependent on the patient or on his clinical state, such as that for example the daily production of IL-6 calculated according to the method described by Lu et al. 3), the proliferation profile, the level of CRP / IL-6, the isotype of the monoclonal protein, the prognostic factors of myeloma, the vital functions, in particular creatinine clearance, hepatic functions, etc.).
- the effective dose can be determined according to the method described by Lu et al (13).
- the dose of HB-EGF inhibitor or of the HB-EGF receptor can be between 10 and 1000 ⁇ g / ml of plasma.
- the dose of IL-6 inhibitor or IL-6 receptor inhibitor can be between 10 and 1000 ⁇ g / mL of plasma.
- the subject of the present invention is a pharmaceutical composition with anti-myeloma action (action inhibiting the proliferation of myeloma) containing, as active principle, an effective amount of at least one HB-EGF inhibitor or at least one inhibitor of HB-EGF receptors, in combination with an acceptable pharmaceutical excipient.
- the pharmaceutical composition according to the invention contains, as active ingredient, an effective amount of at least one inhibitor of HB-EGF or at least one inhibitor of ErbB receptors of HB-EGF, in particular of the receptor ErbB1 or ErbB4 receptor, or at least one inhibitor of transduction pathways in combination with an effective amount of at least one IL-6 inhibitor or at least an IL-6 receptor inhibitor, or an inhibitor of IL-6-induced transduction pathways, said inhibitors being packaged together or separately with a pharmaceutically acceptable vehicle.
- Any conventional pharmaceutically acceptable vehicle can be used, such as for example a solution containing a stabilizer of monoclonal antibody or human albumin, preferably a pharmaceutically acceptable vehicle suitable for parenteral administration is used.
- the invention also relates to a method of treating myeloma which consists in administering to patients with myeloma an effective amount of at least one inhibitor of HB-EGF or of at least one inhibitor of the receptor for HB-EGF or d '' at least one inhibitor of associated transduction pathways optionally in combination with an effective amount of at least one inhibitor of IL-6 or at least one receptor of IL-6 or at least one inhibitor of associated transduction pathways , the administration of said inhibitors being concomitant or sequential, determined according to the data deduced from pharmacological parameters or from clinical data.
- HMCL human myeloma cell lines
- HMCL myeloma cell lines
- LCL lymphoblastoid cell lines
- ATLAS Epstein-Barr virus
- RNA was extracted from each cell and used to synthesize cDNA labeled with a radioactive element ( 32 P).
- the radiolabelled cDNAs were then hybridized to two identical DNA chips according to the technique recommended by Clontech and the radioactivity was analyzed by Phospho Imager (Amersham, Saclay, France). Flow cvtometry analysis
- ErbB1 The expression of ErbB1 was evaluated by incubating 5 ⁇ 10 5 myeloma cells with 0.5 ⁇ g of human monoclonal antibody anti-EGF receptor (anti-EGF-R) (LA1) or a mouse monoclonal antibody not recognizing not human antigens (Immunotech, Marseille, France) in phosphate buffer (PBS) containing 30% AB serum at 4 ° C for 30 minutes. Next, the cells were washed and incubated with a goat anti-mouse monoclonal antibody conjugated with polyethylene glycol (PE) (Immunotech, Marseille, France) in PBS containing 30% AB serum at 4 ° C for 30 minutes.
- PE polyethylene glycol
- the membrane HB-EGF was detected by labeling 5 ⁇ 10 5 myeloma cells with 0.5 ⁇ g of goat anti-human HB-EGF antibody or 1% of goat serum in PBS containing 100 ⁇ g / ml of immunoglobulins (Ig ) at 4 ° C for 30 minutes.
- the cells were washed and incubated with anti-goat pig immunoglobulins conjugated to FITC, in PBS containing 100 ⁇ g / ml at 4 ° C for 30 minutes.
- the percentage of labeled cells and the average fluorescence intensity (IMF) were determined by the flow cytometer of the FACScan type (Becton Dickinson, USA), or others.
- the cells were cultured for 5 days in flat-bottomed 96-well titration microplates at the rate of 10 4 cells / well in culture medium without serum X-VIVO 20. Different concentrations of cytokines or of growth factors or cytokine / growth factor inhibitors were added at the start of culture in 6 culture wells per group. At the end of the culture, the cells were labeled with tritiated thymidine (Amersham, Orsay, France) for 12 hours, harvested and counted according to the procedure described by De Vos et al 0 2 ). Long-term growth of myeloma cells
- the cells were washed once with culture medium, incubated for 5 h at 37 ° C in X-VIVO culture medium 20 and washed again twice.
- the myeloma cells were cultured for 3 to 4 days in flat-bottom microplates at the rate of 3 ⁇ 10 5 cells per well in X-VIVO 20 culture medium with different amounts of IL-6 / HB growth factor. -EGF or inhibitors of IL-6 / growth factor HB-EGF.
- the cells were washed twice with PBS and suspended in a solution of annexin-V-FITC (dilution 1/50 in HEPES buffer: 10mM HEPES / NaOH, pH 7.4 , 140 mM NaCI and 5 mMCaCI 2 ).
- CDNA was produced with 2 ⁇ g total of RNA using the reverse transcriptase Superscript II (Life Technologies) and the oligo d (T) ⁇ 2 -iR (Amersham Pharmacia Biotech) as a primer.
- Each 25 ⁇ l portion of PCR contained 1 ⁇ l of the first strand cDNA, 1 ⁇ M of each primer (sense and antisense), 0.2 mM of each dNTP, 1.5 mM of MgCl 2 , 1 ⁇ polymerase buffer, 2 U of Taq polymerase (Life Technologies) and 1 ⁇ Ci of ⁇ 32 P- dCTP (Amersham Pharmacia Biotech).
- the following primers were used:
- ⁇ 2 -M 5'-CCA GCA GAG AAT GGA AAG TC (sense) and 5'-GAT GCT GCT TAC ATG TCT CG (antisense).
- the sizes of the PCR products were for Tyro3 344 bpd, HB-EGF 605 bpd, FRZB (Frizzled-related receptor B) 599 bpd, ⁇ 2 -M 269 bpd.
- the amplification profile was 1 minute at 94 ° C, 45 seconds at 59 ° C (Tyro3) or 62 ° C (HB-EGF) or 60 ° C (FRZB or ⁇ 2 -M), 1 minute at 72 ° C, operations followed by a final extension of 10 minutes at 72 ° C.
- the number of cycles was 26 for Tyro3, 32 for HB-EGF and 25 for FRZB or ⁇ 2 -M.
- the reaction products were electrophoresed on 4% polyacrylamide gel, dried and exposed to X-ray films.
- HB-EGF is a gene whose expression may be linked to the pathobiology of multiple myeloma (MM). Using DNA chips, the HB-EGF gene was found to be markedly overexpressed in 3 myeloma lines (HMCL: XG-1, XG-7 and XG-14) and in none of the 4 LCLs. The expression of the HB-EGF gene was sought by RT-PCR in the cell lines and in primary cells. HB-EGF mRNA was detected in 3/6 HMCLs, but in none of the 4 LCLs, which confirms the results obtained with the DNA chips.
- HB-EGF mRNA could not be amplified by RT-PCR in malignant plasma cells purified from 4 of 4 PCL cases, strong expression was found in medullary cells purified from 2 patients with MM. In normal plasma cells, low expression was noted in 1 of 4 samples.
- the ErbB1 gene unlike the ErbB4 gene, has been highly expressed in MM cells, as well as in LCL, suggesting that HB-EGF may be an autocrine growth factor for tumor cells, by binding to its Erb-B1 receptor. It was therefore investigated whether blocking the activity of HB-EGF could modulate the proliferation of the cell line of MM XG-1 which has highly expressed the HB-EGF gene.
- Membrane HB-EGF has also been demonstrated on myeloma cells by incubating these incubated cells with anti-HB-EGF goat antibody or control goat serum and then with an anti-goat anti-goat pig antibody conjugated to FITC. The fluorescence was analyzed with a FACScan cytofluorometer. The results are those of an experiment representative of two experiments.
- Example 2 Inhibition by mutated diphtheria toxin of myeloma cell proliferation induced by IL-6
- Myeloma cells (10 4 cells / well) were cultured for 5 days in culture medium without serum X-VIVO 20 with 500 ⁇ g / ml of IL-6 and a progressive concentration of mutated diphtheria toxin (mDT).
- mDT mutated diphtheria toxin
- the results are the mean + SE of the incorporation of tritiated thymidine determined on culture wells in sixfold.
- the results which are shown in FIG. 3 are those of a representative experiment of 3 to 4 experiments, depending on the cell lines. * indicates a statistical difference in the mean value compared to that of the group of cells cultured without mDT or HB-EGF (P ⁇ 0.05, tested with a Student T test). * * indicates a statistical difference in the mean value compared to that of the group of cells cultured with 100 ⁇ g / ml of mDT.
- Figure 3 shows that this autocrine HB-EGF is critical for promoting the growth of 2/4 IL-6 dependent HMCLs, HMCL XG-1 and XG-14.
- mutated diphtheria toxin which is a specific inhibitor of HB-EGF, has decreased the proliferation of HMCL induced by IL-6.
- the inhibitory effect of mDT was compensated by the addition of an excess of recombinant HB-EGF, which indicates that it was not due to non-specific toxicity of the mutated DT (FIG. 3).
- EXAMPLE 3 An HB-EGF Antagonist Does Not Inhibit the Proliferation of Myeloma Cells Cultured with High Concentrations of IL-6 Myeloma Cells (10 4 cells / well) were cultured for 5 days in culture medium without serum X-VIVO 20 (A) with 500 pg / ml or 5 ng / ml of IL-6 and a progressive concentration of mutated diphtheria toxin (mDT), (B) with progressive concentrations of IL-6.
- the results reported in FIG. 4 are means + SD of the incorporation of tritiated thymidine determined on culture wells in sixfold. The results are those of an experiment representative of two experiments.
- Example 4 Induction of apoptosis of mveloma cells by an HB-EGF antagonist Myeloma cells were cultured for 3 days with 500 ⁇ g / ml of IL-6 with or without 100 ⁇ g / ml of mutated diphtheria toxin. In a group, 1 ⁇ g / ml of HB-EGF was added at the start of the culture at the same time 500 pg / ml of IL-6 and 100 ⁇ g / ml of mutated diphtheria toxin. Apoptosis was evaluated by labeling with Pannexin V and analysis by cytofluorimetry. The numbers in the panels indicate the percentage of cells positive for annexin V in apoptosis. The results reported in FIG. 5 are those of the experiment representative of two experiments.
- mDT By means of labeling with annexin V, mDT has been shown to induce apoptosis in the 2 HMCLs XG-1 and XG-14 (FIG. 5), with a majority of myeloma cells (87% and 62%) in apoptosis with 100 ⁇ g / ml of mDT. Apoptosis induced by mDT was compensated by adding a large amount of recombinant HB-EGF capable of counterbalancing mDT (Figure 5).
- Example 5 Expression of ErbB1 on Myeloma Cells
- Myeloma cells were labeled with a monoclonal antibody directed against ErbB1 or a control murine monoclonal antibody recognizing no human antigen. Then, the cells were labeled with a goat anti-murine Ig antibody conjugated to PE. The fluorescence was analyzed with a FACSscan cytofluorimeter. The results reported in FIG. 6 are those of an experiment representative of three experiments.
- EXAMPLE 6 Inhibition by Monoclonal Antibodies Against ErbB1 of the Proliferation of Myeloma Cells Induced by IL-6 Myeloma Cells (10 4 cells / well) were cultured for 5 days in culture medium without serum X-VIVO 20 with 500 ⁇ g / ml of IL-6 and a progressive concentration of an anti-monoclonal antibody ErbBI (0-10 ⁇ g / ml).
- FIG. 7 show that the proliferation of XG-1 and XG-14 cells was strongly inhibited by the anti-ErbB1 antibody at a concentration (10 ⁇ g / ml).
- the inhibitory effect of the anti-ErbB1 monoclonal antibody was compensated for by the addition of a large amount of recombinant HB-EGF.
- the myeloma cell lines do not express the EGF gene (Table 1).
- the strong inhibition of the proliferation of XG-1 and XG-14 cells by the anti-ErbBI monoclonal antibody is consistent with their high expression of the HB-EGF gene, an inhibition marked by HB-EGF antagonists and an expression of ErbBI detectable by FACS.
- the survival and proliferation, induced by IL-6, of the myeloma cell lines XG-1 and XG-14 depends on an autocrine loop HB-EGF / ErbB1.
- Example 7 Inhibition by IL-6 or Anti-ErbBI Monoclonal Antibodies of IL-6-Induced Myeloma Cell Proliferation
- XG-1 Myeloma Cells were Cultured in the Presence of 100 ⁇ g / ml of Interleukin-6 (IL-6) in X-VIVO20 medium for 96 hours.
- IL-6 Interleukin-6
- B-E8 an anti-IL-6 monoclonal antibody
- LA-1 anti-ErbB1 monoclonal antibody
- the results of FIG. 8 show that the anti-ErbBI monoclonal antibody potentiates the inhibitory effect of the anti-IL-6 monoclonal antibody on the IL-6 dependent proliferation of cells.
- Example 8 Expression of CD9 Tetraspanin by Myeloma Lines Myeloma cells were cultured for 2 days in X-VIVO 20 culture medium with 0.2 ng / ml or 2 ng / ml of IL-6, and l CD9 expression was assessed by labeling with an anti-CD9 monoclonal antibody conjugated to phycoerythrin. The percentage of labeled cells and the mean fluorescence intensity (IMF) were determined using a FASCscan cytofluorimeter. The results are those of an experiment among two representative experiments.
- IMF mean fluorescence intensity
- the MFI obtained with the control antibody of the corresponding isotype was fixed between 3 and 5.
- the results in Table 2 show that the lines XG-1 and XG-14 strongly express the tetraspanin CD9. This expression is not regulated by IL-6.
- the XG-1 and XG-13 lines express it very weakly.
- Tetraspanin CD9 being a receptor of HB-EGF, capable of very strongly increasing its biological activity, these data reinforce the importance of an autocrine loop CD9 / HB- EGF / Erb-B1 in controlling the proliferation of XG lines -1 and XG-14 mediated by IL-6.
- IL-6 MFI cells MFI cells Cells : IMF. '' IMF ⁇ ' ⁇ cells viable viable viable viable marked marked marked (%) marked () marked (%):
- Myeloma cells (10 4 cells / well) were cultured for 5 days in culture medium without serum X-VIVO 20 with 500 ⁇ g / ml of IL-6 and 50 ⁇ g / ml of anti-CD9 SYB-1 mAb .
- 1 ⁇ g / ml of recombinant HB-EGF was added at the start of the culture at the same time as 10 ⁇ g / ml of anti-CD9 SYB-1 mAb and 500 ⁇ g / ml of IL-6.
- results are averages + SD of the incorporation of tritiated thymidine determined on six-fold culture wells.
- the results are those of an experiment representative of two experiments. * indicates a statistical difference in the mean compared to that of the group of cultured cells without anti-CD9 or HB-EGF mAb (P ⁇ 0.05, tested with a Student T test).
- the anti-CD9 SYB-1 monoclonal antibody could block the proliferation of XG-1 myeloma cells. This inhibition was compensated by the addition of a large amount of recombinant HB-EGF which can compete with the anti-CD9 monoclonal antibody for binding to CD9.
- Myeloma XG-1 or XG-14 cells were cultured at a rate of 10 5 cells / ml in culture medium without serum X-VIVO 20 with 10 ⁇ g / ml of a murine monoclonal antibody recognizing no human antigen and without cytokine, or with 500 pg / ml of IL-6 or 100 ng / ml of recombinant HB-EGF.
- 10 ⁇ g / ml of neutralizing IL-6 gp130 B-R3 anti-transducer monoclonal antibody or neutralizing anti-ErbB1 LA-1 monoclonal antibody were added.
- Recombinant HB-EGF promoted the survival of XG-1 and XG-14 myeloma cells and growth that was lower than that induced by IL-6.
- the weak growth of recombinant HB-EGF-mediated myeloma cells was inhibited by the anti-ErbB1 monoclonal antibody. It was also completely inhibited by the neutralizing anti-gp130 monoclonal antibody.
- This autocrine expression of the IL-6 gene was also detected with the ATLAS DNA chips in XG-1 cells and in the other myeloma cell lines (see Table 1) and confirmed by RT-PCR ( Figure 11).
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Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/484,819 US20040254144A1 (en) | 2001-08-01 | 2002-08-01 | Use of inhibitors of heparin-binding epidermal growth factor or inhibitors of its receptors for the preparation of drugs useful for treating myeloma |
CA002459071A CA2459071A1 (fr) | 2001-08-01 | 2002-08-01 | Utilisation des inhibiteurs du facteur de croissance epidermique se liant 'a l'heparine ou de ses inhibiteurs de ses recepteurs dans la preparation de medicaments utiles pour traiter le myelome |
EP02794618A EP1411907A1 (fr) | 2001-08-01 | 2002-08-01 | Inhibiteurs des recepteurs de hb-egf (erbb) pour traiter le myelome |
JP2003518495A JP2005504038A (ja) | 2001-08-01 | 2002-08-01 | ヘパリン結合性上皮増殖因子阻害剤又はその受容体の阻害剤の、骨髄腫の治療に有用な薬剤の調製のための使用 |
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FR01/10354 | 2001-08-01 | ||
FR0110354A FR2828104B1 (fr) | 2001-08-01 | 2001-08-01 | Utilisation d'inhibiteurs du facteur de croissance epidermique liant l'heparine ou d'inhibiteurs de ses recepteurs pour la preparation de medicaments utiles pour traiter le myelome |
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WO2003013485A1 true WO2003013485A1 (fr) | 2003-02-20 |
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US (1) | US20040254144A1 (fr) |
EP (1) | EP1411907A1 (fr) |
JP (1) | JP2005504038A (fr) |
CA (1) | CA2459071A1 (fr) |
FR (1) | FR2828104B1 (fr) |
WO (1) | WO2003013485A1 (fr) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2005004893A3 (fr) * | 2003-07-04 | 2005-02-10 | Max Planck Gesellschaft | Inhibition de l'activite du recepteur egfr qui est ligand-dependante et induite par le stress |
AU2008249216B2 (en) * | 2002-03-08 | 2012-01-19 | Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. | Use of EGFR transactivation inhibitors in human cancer |
RU2504551C2 (ru) * | 2007-09-26 | 2014-01-20 | УЗ ФАРМА ГмбХ | Белки, связывающие антиген фактор роста, подобный гепаринсвязывающему эпидермальному фактору роста |
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US4757056A (en) * | 1984-03-05 | 1988-07-12 | Hepar Industries, Inc. | Method for tumor regression in rats, mice and hamsters using hexuronyl hexosaminoglycan-containing compositions |
US5366874A (en) * | 1992-01-02 | 1994-11-22 | Board Of Regents, The University Of Texas System | Molecular cloning and expression of biologically-active diphtheria toxin receptor |
WO1999007407A1 (fr) * | 1997-08-07 | 1999-02-18 | Childrens Hospital Research Foundation | Polypeptides du facteur de croissance se fixant a heparine (hbgf) |
US6090794A (en) * | 1990-04-19 | 2000-07-18 | The General Hospital Corporation | Inhibition of neurofibrosarcoma growth and angiogenesis |
US6172042B1 (en) * | 1995-09-28 | 2001-01-09 | Yeda Research And Development Co. Ltd | Synthetic peptides that inhibit IL-6 activity |
US6235884B1 (en) * | 1993-06-15 | 2001-05-22 | Scios Nova, Inc. | Heparin binding mitogen with homology to epidermal growth factor (EGF) |
Family Cites Families (2)
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EP2359849A1 (fr) * | 2001-04-02 | 2011-08-24 | Genentech, Inc. | Polytherapie |
JP2005500034A (ja) * | 2001-06-20 | 2005-01-06 | プロション バイオテク リミテッド | 受容体型タンパク質チロシンキナーゼ活性化を遮断する抗体、そのスクリーニング方法、及びその使用 |
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- 2002-08-01 JP JP2003518495A patent/JP2005504038A/ja active Pending
- 2002-08-01 US US10/484,819 patent/US20040254144A1/en not_active Abandoned
- 2002-08-01 EP EP02794618A patent/EP1411907A1/fr not_active Withdrawn
- 2002-08-01 CA CA002459071A patent/CA2459071A1/fr not_active Abandoned
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US4757056A (en) * | 1984-03-05 | 1988-07-12 | Hepar Industries, Inc. | Method for tumor regression in rats, mice and hamsters using hexuronyl hexosaminoglycan-containing compositions |
US6090794A (en) * | 1990-04-19 | 2000-07-18 | The General Hospital Corporation | Inhibition of neurofibrosarcoma growth and angiogenesis |
US5366874A (en) * | 1992-01-02 | 1994-11-22 | Board Of Regents, The University Of Texas System | Molecular cloning and expression of biologically-active diphtheria toxin receptor |
US6235884B1 (en) * | 1993-06-15 | 2001-05-22 | Scios Nova, Inc. | Heparin binding mitogen with homology to epidermal growth factor (EGF) |
US6172042B1 (en) * | 1995-09-28 | 2001-01-09 | Yeda Research And Development Co. Ltd | Synthetic peptides that inhibit IL-6 activity |
WO1999007407A1 (fr) * | 1997-08-07 | 1999-02-18 | Childrens Hospital Research Foundation | Polypeptides du facteur de croissance se fixant a heparine (hbgf) |
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CHADWICK D.E. ET AL: "Differential sensitivity of human myeloma cell lines and normal bone marrow colony forming cell to a recombinant diphtheria toxin- interleukin 6 fusion protein.", BRITISH JOURNAL OF HAEMATOLOGY, (1993) 85/1 (25-36)., XP008002427 * |
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IWAMOTO R ET AL: "HEPARIN-BINDING EGF-LIKE GROWTH FACTOR, WHICH ACTS ARE THE DIPHTHERIA TOXIN RECEPTOR, FORMS A COMPLEX WITH MEMBRANE PROTEIN DRAP27/CD9, WHICH UP-REGULATES FUNCTIONAL RECEPTORS AND DIPHTHERIA TOXIN SENSITIVITY", EMBO JOURNAL, OXFORD UNIVERSITY PRESS, SURREY, GB, vol. 10, no. 13, 1994, pages 2322 - 2330, XP001064892, ISSN: 0261-4189 * |
KAWANO ET AL.: "Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas", NATURE, vol. 332, 3 March 1988 (1988-03-03), pages 83 - 85, XP002199052 * |
LEVY ET AL.: "Retinoic acid modulates the in vivo and in vitro growth of IL-6 autocrine human myeloma cell lines via induction of apoptosis", CLIN. EXP. IMMUNOLOGY, vol. 104, no. 1, April 1996 (1996-04-01), pages 167 - 172 * |
MITAMURA T ET AL: "DIPHTHERIA TOXIN BINDS TO THE EPIDERMAL GROWTH FACTOR (EGF)-LIKE DOMAIN OF HUMAN HEPARIN-BINDING EGF-LIKE GROWTH FACTOR/DIPHTHERIA TOXIN RECEPTOR AND INHIBITS SPECIFICALLY ITS MITOGENIC ACTIVITY", JOURNAL OF BIOLOGICAL CHEMISTRY, AMERICAN SOCIETY OF BIOLOGICAL CHEMISTS, BALTIMORE, MD, US, vol. 270, no. 3, 20 January 1995 (1995-01-20), pages 1015 - 1019, XP002912324, ISSN: 0021-9258 * |
PUTHIER ET AL.: "Myeloma cell growth arrest, apoptosis, and interleukin-6 receptor modulation induced by EB1089, a vitamin D3 derivative, alone or in association with dexamethasone", BLOOD, vol. 88, no. 12, 15 December 1996 (1996-12-15), pages 4659 - 4666 * |
RAAB G ET AL: "HEPARIN-BINDING EGF-LIKE GROWTH FACTOR", BIOCHIMICA ET BIOPHYSICA ACTA, AMSTERDAM, NL, vol. 1333, no. 3, 1997, pages E179 - E199, XP000961069, ISSN: 0006-3002 * |
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See also references of EP1411907A1 * |
SHALLAL ET AL.: "CD9 expression enhances the susceptibility of myeloma cell lines to cell-mediated cytolysis", BLOOD, vol. 96, no. 1, July 2000 (2000-07-01), pages 224 - 233, XP002199051 * |
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2008249216B2 (en) * | 2002-03-08 | 2012-01-19 | Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. | Use of EGFR transactivation inhibitors in human cancer |
WO2005004893A3 (fr) * | 2003-07-04 | 2005-02-10 | Max Planck Gesellschaft | Inhibition de l'activite du recepteur egfr qui est ligand-dependante et induite par le stress |
JP2009513515A (ja) * | 2003-07-04 | 2009-04-02 | マックス−プランク−ゲゼルシャフト・ツア・フェルデルング・デア・ヴィッセンシャフテン・エー・ファオ | ストレス誘導性リガンド依存性egfr活性化の阻害 |
EP2275115A3 (fr) * | 2003-07-04 | 2011-04-06 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Inhibition de l'activation de l'EGFR, cette activation étant dépendante d'un ligand et étant induite par le stress |
JP2011084580A (ja) * | 2003-07-04 | 2011-04-28 | Max-Planck-Ges Zur Foerderung Der Wissenschaften Ev | ストレス誘導性リガンド依存性egfr活性化の阻害 |
RU2504551C2 (ru) * | 2007-09-26 | 2014-01-20 | УЗ ФАРМА ГмбХ | Белки, связывающие антиген фактор роста, подобный гепаринсвязывающему эпидермальному фактору роста |
Also Published As
Publication number | Publication date |
---|---|
FR2828104B1 (fr) | 2005-06-24 |
EP1411907A1 (fr) | 2004-04-28 |
CA2459071A1 (fr) | 2003-02-20 |
FR2828104A1 (fr) | 2003-02-07 |
US20040254144A1 (en) | 2004-12-16 |
JP2005504038A (ja) | 2005-02-10 |
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