WO2004085479A2 - Treatment of viral infections - Google Patents
Treatment of viral infections Download PDFInfo
- Publication number
- WO2004085479A2 WO2004085479A2 PCT/EP2004/003245 EP2004003245W WO2004085479A2 WO 2004085479 A2 WO2004085479 A2 WO 2004085479A2 EP 2004003245 W EP2004003245 W EP 2004003245W WO 2004085479 A2 WO2004085479 A2 WO 2004085479A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- trail
- inhibitor
- receptor
- trail receptor
- ligand
- Prior art date
Links
Classifications
-
- 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
- C07K16/2875—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70575—NGF/TNF-superfamily, e.g. CD70, CD95L, CD153, CD154
-
- 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
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70578—NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
-
- 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
- C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
Definitions
- the present invention relates to the use of inhibitors of the TRAIL ligand/TRAIL receptor system for the manufacture of a medicament for the prevention or treatment of viral diseases, particularly for the prevention or treatment of influenza or Borna disease virus infections.
- NF-/.B is activated by multiple families of viruses, including HIV-1 , HTLV-1 , Hepatitis B and C viruses, EBV, VSV and influenza viruses 1 . While for some of these viruses, e.g. retroviruses or oncogenic viruses, activation of this transcription factor may support viral replication, it is a common view that NF-/ 3 acts in an antiviral fashion upon infection with RNA viruses, such as VSV or influenza virus 2,3 . RNA virus infections commonly result in activation of an innate antiviral response mediated by type I interferons (IFNs). This antiviral program is initiated by viral induction of the IFN ⁇ gene through constitutively expressed transcription factors, namely AP-1 , IRF-3 and NF-/.B 4 .
- IFNs type I interferons
- IFN ⁇ also other genes involved in the induction of inflammation and immune responses are also regulated by NF-/.B, such as IL-6, TNF- ⁇ or IL-12. Accordingly, VSV-induced expression of IFN ⁇ , IL-6 and IL-12 is impaired in cells deficient for the NF-/.B activator B-kinase 2 (IKK2) 2 .
- IKK2 NF-/.B activator B-kinase 2
- NF- B is mainly regarded as a survival factor by up-regulating antiapoptotic genes, such as Bcl-XL, A20 or clAPs 5,6 .
- NF-/.B was also reported to act proapoptotically under certain conditions, e.g. by upregulating the death-inducing CD95 ligand and its receptor 5,6 .
- the concept of a context-dependent regulation of apoptosis by NF- .B has emerged 6 .
- RNA viruses produce dsRNA-like replication intermediates representing a shared molecular pattern that may be sensed by the cell as an alert signal 9 .
- NF- .B dependent viral induction is mediated via the proapoptotic factor TRAIL which enhances virus propagation in an auto- and paracrine fashion, particularly in the context of an influenza virus infection.
- a first aspect of the present invention relates to the use of inhibitors of the TRAIL ligand/receptor system for the manufacture of a medicament for the treatment of viral infections, particularly for the treatment of viral infections caused by RNA viruses e.g. negative strand RNA viruses such as influenza viruses and Borna disease viruses. Especially preferred is the prevention or treatment of influenza virus infections.
- the TRAIL ligand/TRAIL receptor inhibitors are used for the prevention or treatment of viral infection in humans or in domestic or wild animals, e.g. horses or sheep.
- the inhibitors of the present invention may be administered for the prevention of viral infections and/or for the treatment of acute or chronic viral infections.
- the inhibitor is a TRAIL (TRAIL ligand APO-2) inhibitor.
- TRAIL inhibitors may be selected from
- inhibitory anti-TRAIL-antibodies and antigen binding fragments thereof and soluble TRAIL receptor molecules or TRAIL ligand binding portions thereof are preferred.
- suitable anti-TRAIL antibodies are monoclonal antibodies, chimeric, humanized or human antibodies or antibody fragments, e.g. proteolytic fragments or recombinant single-chain fragments. These antibodies may be obtained by immunization and selection procedures known in the art.
- soluble TRAIL receptor molecules e.g. a soluble TRAIL receptor molecule without the transmembrane domain 28 or TRAIL receptor peptides which are capable of binding to TRAIL.
- the TRAIL receptor molecule may be selected from TRAIL receptor-1 , (TRAIL-R1 , DR4), TRAIL receptor-2 (TRAIL-R2, Apo2, DR5, KILLER, TRICK2a, TRICK2b), TRAIL receptor-3 (DCR1 ), TRAIL receptor-4 (DCR2, TRUND) and OPG (osteoprotegerin).
- TRAIL receptor-1 and the TRAIL receptor-2 more preferred is the TRAIL receptor-2.
- TRAIL receptors are described in WO 98/32856, WO 98/35986, WO 98/41629, WO 99/10484, WO 00/66156 and reference 28, which are incorporated herein by reference.
- TRAIL inhibitor which comprises an extracellular domain of a TRAIL receptor molecule.
- the extracellular domain is optionally fused to a heterologous polypeptide domain, particularly a Fc immunoglobulin molecule including the CH2 and the CH3 domain and optionally the hinge region e.g. from the human lgG1 molecule.
- the inhibitor is a TRAIL receptor inhibitor which may be selected from
- inhibitory anti-TRAIL receptor antibodies e.g. antibodies against TRAIL receptor-1 , TRAIL receptor-2, TRAIL receptor-3, TRAIL receptor-4 or OPG, and inhibitory TRAIL ligand fragments are described in WO 98/35986, WO 99/10484, WO 00/73349, reference 31 and reference 32, which are incorporated herein by reference.
- the antibodies may be monoclonal, chimeric, humanized or human antibodies or proteolytic or recombinant antibody fragments.
- anti-TRAIL R1 and anti-TRAIL R2 antibodies are especially preferred.
- the inhibitor is capable of inhibiting the interaction of the Death domain of TRAIL receptor-1 or TRAIL receptor-2 with the Death domain of FADD.
- suitable inhibitors are antibodies or fragments which are specifically directed against the Death domain of TRAIL-R1 , TRAIL-R2 or FADD.
- the inhibitor may be capable of inhibiting the interaction between the Death Effector domain of FADD and caspase-8 and/or caspase-10, thereby inhibiting death receptor, e.g. TRAIL receptor induced processes, e.g. apoptotic processes.
- death receptor e.g. TRAIL receptor induced processes, e.g. apoptotic processes.
- the inhibitor is a nucleic acid effector molecule.
- the nucleic acid effector molecule may be selected from anti-sense molecules, RNAi molecules and ribozymes which are capable of inhibiting the expression of at least one TRAIL receptor gene and/or the TRAIL ligand gene.
- the inhibitor may be directed against intracellular TRAIL receptor signal transduction e.g. specific inhibitors of TRAIL receptor signal transduction or general inhibitors of apoptotic signal transduction.
- intracellular inhibitors are selected from apoptosis inhibitors, particularly intracellular apoptosis inhibitors, e.g. caspase inhibitors such as caspase-3, caspase-8 or caspase-10 inhibitors, Bid inhibitors, Bax inhibitors or any combination thereof.
- suitable inhibitors are caspase inhibitors in general, cf.
- WO 02/094263 WO 01 /10383, WO 01 /42216, WO 01 /90070, WO 01 /94351 , WO 01 /21600, WO 00/61542, WO 99/47545, dipeptide inhibitors (WO 99/47154) , carbamate inhibitors (WO 01/72707) , substituted aspartic acid acetals (WO 01/81330), heterocyclyldicarbamides (WO 02/085899), quinoline-(di-, tri-, tetrapeptide) derivatives (US 200126467), substituted 2- aminobenzamide caspase inhibitors (WO 00/551 14), substituted ⁇ -hydroxy acid caspase inhibitors (WO 01 /16093) inhibition by nitrosylation (WO 98/43621 ); CASP-1 : (WO 02/000853; CASP-3: protein-inhibitors (WO 02/066050), antisense molecules (WO 01/53310), nicotinyl-as
- mitochondrial inhibitors such as Bcl-2-modulating factor (WO 02/097094); Bcl-2 (WO 94/27426) mutant peptides derived from Bad (WO 02/20568), Bad (WO 96/13614), BH3-interacting domain death agonist (WO 98/09980), Bax inhibitor proteins (WO 98/40397), BLK genes and gene products (WO 99/50414) which are herein incorporated by reference.
- Suitable intracellular modulators of apoptosis are modulators of CASP9/Apaf-1 association (WO 02/0641 28), antisense modulators of Apaf-1 expression (WO 02/32921 ), peptides for inhibition of apoptosis (WO 99/43701 ), anti- apoptotic compositions comprising the R1 subunit of Herpes Simplex virus (WO 00/07618), MEKK1 and fragments thereof (WO 99/41385), modulators of Survivin (WO 01 /64741 ), modulators of inhibitors of apoptosis (WO 97/061 82, WO 00/77201 , WO 01 /59108, WO 02/053586) and HIAP2 (WO 00/08144) which are herein incorporated by reference. Further, any combination of the above inhibitors may be used.
- the inhibitor or a combination of the above inhibitors is administered to a subject in need thereof, particularly a human patient, in a sufficient dose for the treatment of the specific condition by suitable means.
- the inhibitor may be formulated as a pharmaceutical composition together with pharmaceutically acceptable carriers, diluents and/or adjuvants.
- Therapeutic efficacy and toxicity may be determined according to standard protocols.
- the pharmaceutical composition may be administered systemically, e.g. intraperitoneally, intramuscularly or intravenously, or locally, e.g. intranasally. Preferred is intravenous and/or intranasal administration.
- An especially preferred combination of inhibitors is an extracellular TRAIL/TRAIL receptor inhibitor, e.g. an anti-TRAIL antibody or a soluble extracellular TRAIL receptor domain optionally fused to a heterologous polypeptide, and an intracellular TRAIL receptor signal transduction inhibitor.
- an extracellular TRAIL/TRAIL receptor inhibitor e.g. an anti-TRAIL antibody or a soluble extracellular TRAIL receptor domain optionally fused to a heterologous polypeptide, and an intracellular TRAIL receptor signal transduction inhibitor.
- a further active ingredient is present, which may be selected from antiviral agents such as amantadine and derivatives thereof which are directed against viral transmembrane proteins, e.g. rimantadine, inhibitors of viral neuraminidases, particularly neuraminidase from influenza virus, e.g. relanza, inhibitors of the Raf-MeK-Erk signal transduction pathway, e.g. 201 26 or further inhibitors as described in PCT/DE 01 /01 292, inhibitors of the MIKK/SEK/YMK signal transduction pathway or components of further signal transduction pathways as described in DE 1 01 3891 2 and synthetic nucleoside analoga such as 3-dea ⁇ aadenozine and ribavirine.
- antiviral agents such as amantadine and derivatives thereof which are directed against viral transmembrane proteins, e.g. rimantadine, inhibitors of viral neuraminidases, particularly neuraminidase from influenza virus
- the dose of the inhibitor administered will of course, be dependent on the subject to be treated, on the subject's weight, the type and severity of the injury, the manner of administration and the judgement of the prescribing physician.
- a daily dose of 0,001 to 1 00 mg/kg is suitable.
- Still a further aspect of the present invention is a method of identifying and/or characterizing inhibitors of viral infections, particularly infections by RNA viruses such as influenza or Borna disease virus, comprising determining if a compound is capable of inhibiting the TRAIL ligand/TRAIL receptor system.
- the inhibition of the TRAIL ligand /TRAIL receptor system preferably comprises an inhibition of TRAIL ligand/TRAIL receptor mediated apoptosis or a TRAIL ligand/TRAIL receptor mediated cell activation.
- the method as described above may be a molecular-based assay, wherein the effect of a compound to be tested on the interaction between a TRAIL ligand and a TRAIL receptor is analyzed in a test system comprising substantially purified and isolated components, e.g. recombinant molecules.
- the method may be carried out as a cellular-based assay, wherein a suitable test cell, e.g. a test cell expressing or overexpressing a TRAIL receptor is used.
- Suitable molecular- and cellular- based assay systems e.g. high throughput assay systems are known in the art.
- FIG. 1 IMF- ⁇ B signalling is important for efficient influenza virus production
- a) Immunoblot analysis of ⁇ a degradation A549 cell lines stably expressing vector, 1KK2 EE, IKK2 KD or B mut were stimulated with TNF- ⁇ (20ng/ml) and harvested after indicated times. Note that overexpressed B ⁇ rmut shows a retardation in SDS Gel. IKK EE cell lines do not show a constitutive ⁇ Ba degradation, however, recovery of de novo ⁇ Ba expression upon stimulation is faster. This may be the basis of enhanced NF- B signal strength consistently observed in stimulated or infected IKK2 EE cells. b) NF-/cB promoter-luciferase-reportergene-assay.
- Data are shown as percentage of virus titers compared to the vector control. Each bar represents the average and standard deviation of three independent experiments. e) Experiments were performed as described in d using the different A549 cell lines infected with FPV. Data are shown as absolute plaque forming units in a logarithmic scale. Each bar represents the average and standard deviation of three independent experiments.
- FIG. 2 NF- ⁇ B acts proapoptotic in A549 cell lines in the context of an influenza virus infection.
- TRAIL is an important mediator for influenza A virus propagation.
- Soluble TRAIL-R2-Fc prevents TRAIL-mediated caspase activation.
- A549 cells were either left untreated or stimulated with recombinant flag-tagged human TRAIL (20ng/ml) with or without soluble TRAIL- receptor 2 (TRAIL-R2-Fc, 10 /g/ml) for 1 6h. Lysates were subjected to an anti-PARP Western blot as a measure for apotosis induction.
- Presence of TRAIL-R2-Fc results in decreased influenza virus production.
- TNF-R2-Fc prevents TNF ⁇ induced ⁇ Ba degradation.
- A549 cells were either left untreated or stimulated with recombinant TNF ⁇ (20ng/ml) in the presence or absence of TNF-R2-Fc ( 10 ⁇ g/ml) .
- Avian influenza virus A/Bratislava/79 (H7N7; fowl plague virus (FPV)) was taken from the virus strain collection of the Institute of Virology, Giessen, and was used for infection of different cell lines.
- Madin-Darby canine kidney (MDCK) cells and african green monkey kidney cells (Vero) were grown in minimal-essential medium (MEM) supplemented with 10% heat- inactivated fetal bovine serum (FBS) and antibiotics.
- FBS heat- inactivated fetal bovine serum
- A549 human lung carcinoma cells were grown in Ham ' s F1 2 medium supplemented with 1 0% heat-inactivated FBS and antibiotics.
- A549, MDCK and Vero cell lines stably expressing transdominant m ⁇ B ⁇ as well as constitutively active and dominant negative IKK2 were generated with a retroviral transduction approach using the pCFG5-IEGZ retroviral vector system 27 and amphotrophic Phoenix producer cell lines essentially as described in Denk et al. 16 .
- MOI multiplicities of infection
- PBS/BA PBS containing 0,2% BSA, 1 mM MgCI 2 , 0,9mM CaCI 2 , 100U/ml penicillin and 0, 1 mg/ml streptomycin
- the inoculum was aspirated and cells were incubated with either MEM or Ham 's F1 2 containing 0,2% BSA and antibiotics. 9h or 24h p.i. supernatants were collected to assess the number of infectious particles (plaque titers) in the samples. Briefly, MDCK-cells grown 90% confluent in 6-well dishes were washed with PBS and infected with serial dilutions of the supernatants in PBS/BA for 1 h at 37 °C.
- the inoculum was aspirated and cells were incubated with 2ml MEM/BA (medium containing 0.2% BSA and antibiotics) supplemented with 0.6% Agar (Oxoid), 0.3% DEAE-Dextran (Pharmacia Biotech) and 1 .5% NaHCO 3 at 37 °C, 5% CO 2 for 2-3 days. Virus plaques were visualised by staining with neutral-red. 1 .2 Inhibitors, antibodies and reagents
- Caspase-inhibitor Z-VAD-FMK or inhibitor control Z-FA-FMK were supplied ready-to-use 2mM in DMSO. DMSO was used as solvent control at a final concentration of 2%, representing highest inhibitor concentration.
- the mouse anti-PARP monoclonal antibody was purchased from Transduction Laboratories.
- a monoclonal antibody (mAb) against human TRAIL was purchased from Santa Cruz Biotechnology (sc-8440) .
- the IFN ⁇ -promotor-luciferase plasmid was kindly provided by J.Hiscott, Montreal, Canada.
- the 3xNF-/ B reporter plasmid was described previously 1 3.
- MDCK cells were transfected with Lipofectamine 2000 (LifeTechnologies) according to a protocol by Basler et al. 29 . Luciferase- reporter gene assays were carried out as described earlier 25,30 .
- TRAIL was detected by an intracellular staining procedure.
- A549 cell lines were infected with FPV at an MOI of 5 for 8h in the presence of 2 M monensin to avoid protein secretion.
- Cells were fixed with 4% paraformaldehyde at 4°C for 20 min and subsequently washed twice in permeabilization buffer (0.1 % saponin/1 % fetal calf serum/PBS).
- permeabilization buffer 0.1 % saponin/1 % fetal calf serum/PBS.
- Becton Dickinson After incubation with a mouse monoclonal antibody against TRAIL or isotype control antibodies (Becton Dickinson) cells were stained with biotin-Sp- conjugated goat anti-mouse IgG (Dianova) and streptavidine-Cy-chrome (Becton Dickinson). Fluorescence was determined in the FL3-channel using a FACScalibur cytometer (Becton Dickin
- A549 cell lines were mock infected or infected with FPV at a MOI of 1 .
- 24h p.i. cells were lysed and RNA was isolated using the TRIzol reagent (Invitrogen) according to the manufacturers instructions. Purified RNA was subjected to the RiboQuant Multi-Probe RNase Protection Assay hAPO-3 (BD-Pharmingen) according to the manufacturers instructions.
- IKK KD dominant negative 1KK2
- IKK EE constitutively active IKK2
- ⁇ Ba non- degradable mutant of ⁇ Ba (./.B ⁇ rmut) 16 which prevents NF-/.B activation.
- Figure 1 shows that expression of IKK KD or B ⁇ mut resulted in an efficient block of NF- ⁇ B activation.
- TNF- ⁇ -induced ⁇ Ba degradation Fig.1 a
- influenza virus-induced transcription from a NF-/ B dependent promoter element Fig. 1 b
- Fig. 1 a TNF- ⁇ -induced ⁇ Ba degradation
- Fig. 1 b influenza virus-induced transcription from a NF-/ B dependent promoter element
- IFN ⁇ promoter/enhanceosome the different mutants showed essentially the same effects on transcriptional activation (Fig. 1 c), although less pronounced due to involvement of other virus-induced transcription factors for IFN ⁇ expression. This is consistent with earlier reports suggesting that NF-ztB regulates IFN ⁇ expression as an antiviral function 2 .
- Virus propagation was impaired upon NF- .B inhibition and enhanced in cells expressing the active form of IKK EE (Fig. 1 d,e).
- the effects were similar in Madine Darby canine kidney (MDCK) epithelial cells and in Vero cells (Fig 1 d).
- MDCK Madine Darby canine kidney
- Vero cells Fig 1 d
- the latter cell line does not express type 1 interferons 17 excluding a prominent involvement of these cytokines in the observed effects.
- Inhibition or enhancement of virus propagation correlated with the efficacy of transgene action (data not shown) and was strongest in A549 lung epithelial cells, where the differences in virus titers between the different cell lines were up to 10-fold (Fig. 1 e).
- NF- .B is a transcription factor, thus, the underlying mechanism most likely involves regulation of a proviral acting factor. Since NF-7.B is a regulator of both pro- and antiapoptotic genes 6 we examined viral induction of apoptosis in the different NF-/.B cell lines. To monitor an early apoptotic event we chose proteolytic cleavage of a major caspase substrate, poly (ADP-ribose) polymerase (PARP). Influenza virus infection leads to a significant cleavage of PARP in vector cell lines which was further enhanced in IKK EE expressing cells (Fig. 2a).
- PARP poly (ADP-ribose) polymerase
- NF-/cB acts in a proapoptotic rather than an antiapoptotic fashion in the context of an influenza virus infection.
- apoptosis induction and caspase activation appear to be required for efficient virus propagation.
- Virus yields were strongly impaired in the presence of the pan-caspase inhibitor Z-VAD-FMK, but not by the inactive analogue Z-FA-FMK, both in A549 and in Vero cells (Fig. 2b, c).
- apoptosis regulators such as caspase 8, Fas (APO-1 , CD95), death receptor 3 (DR3), TRAIL or TNF-R1 in vector, IKK EE or IKK KD expressing cell lines using RNAse protection assays (Fig. 3a).
- TRAIL TNF-related apoptosis-inducing ligand
- the apoptosis inducer TRAIL is a proviral factor that is induced in influenza virus infected cells in a NF- .B-dependent manner.
- NF-/.B rather acts proviral in the context of an influenza virus infection at least by regulating expression of the proapoptotic factor TRAIL.
- TRAIL and/or TRAIL-R1 /2 have been shown to be upregulated during infections with several other viruses 20"23 and it has been proposed that this is an antiviral response to selectively kill infected cells or cells of the immune system.
- our data clearly indicate that in the case of influenza virus infection NF-/cB dependent TRAIL induction and subsequent TRAIL mediated apoptosis are proviral events. It therefore seems that influenza virus has acquired the capability to take advantage of the host cells protection machinery and thereby supporting viral replication. It is easier for a viral invader to take advantage of existing cellular activities rather than actively inducing such processes in the host-cell.
- a balance control may be provided by the viral NS1 protein which keeps activities of certain transcription factors in a tolerated limit 3,24,25 thereby preventing an overflow of an antiviral response but still allowing some proviral proteins to be produced.
- recombinant TRAIL only enhanced virus propagation if cells were stimulated late in infection in concentrations up to 10-20 ng/ml (Fig. 4d)
- Earlier stimulation or higher concentrations of TRAIL resulted in a loss of the supportive effects (data not shown).
- This late requirement of TRAIL correlates well with the expression kinetics of the protein during the virus replication cycle (Fig. 3c).
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Virology (AREA)
- Gastroenterology & Hepatology (AREA)
- Cell Biology (AREA)
- Communicable Diseases (AREA)
- Toxicology (AREA)
- Zoology (AREA)
- Oncology (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Cardiology (AREA)
- Pulmonology (AREA)
- AIDS & HIV (AREA)
- Pain & Pain Management (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Transplantation (AREA)
- Biomedical Technology (AREA)
- Vascular Medicine (AREA)
- Tropical Medicine & Parasitology (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2004224123A AU2004224123A1 (en) | 2003-03-26 | 2004-03-26 | Treatment of viral infections |
EP04723556A EP1606319A2 (en) | 2003-03-26 | 2004-03-26 | Treatment of viral infections |
JP2006504879A JP2007533595A (en) | 2003-03-26 | 2004-03-26 | Treatment of viral infection |
CA002520254A CA2520254A1 (en) | 2003-03-26 | 2004-03-26 | Treatment of viral infections |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP03006949.6 | 2003-03-26 | ||
EP03006949 | 2003-03-26 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2004085479A2 true WO2004085479A2 (en) | 2004-10-07 |
WO2004085479A3 WO2004085479A3 (en) | 2004-11-25 |
Family
ID=33040920
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2004/003239 WO2004085478A2 (en) | 2003-03-26 | 2004-03-26 | Improved fc fusion proteins |
PCT/EP2004/003245 WO2004085479A2 (en) | 2003-03-26 | 2004-03-26 | Treatment of viral infections |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2004/003239 WO2004085478A2 (en) | 2003-03-26 | 2004-03-26 | Improved fc fusion proteins |
Country Status (15)
Country | Link |
---|---|
US (2) | US8007813B2 (en) |
EP (2) | EP1606318B1 (en) |
JP (2) | JP4741464B2 (en) |
AT (1) | ATE438662T1 (en) |
AU (2) | AU2004224123A1 (en) |
CA (2) | CA2520254A1 (en) |
CY (1) | CY1109536T1 (en) |
DE (1) | DE602004022390D1 (en) |
DK (1) | DK1606318T3 (en) |
ES (1) | ES2327409T3 (en) |
HK (1) | HK1077592A1 (en) |
PL (1) | PL1606318T3 (en) |
PT (1) | PT1606318E (en) |
SI (1) | SI1606318T1 (en) |
WO (2) | WO2004085478A2 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008528678A (en) * | 2005-02-03 | 2008-07-31 | コーダ セラピューティクス リミテッド | Anti-connexin compounds and their use |
WO2011101031A1 (en) * | 2010-02-19 | 2011-08-25 | Université de Liège | A polynucleotide for use in treatment of influenza a virus induced diseases, encoding modified mx protein, said modified mx protein, and a transgenic animal expressing gene encoding modified mx protein |
Families Citing this family (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE602005021811D1 (en) | 2004-09-13 | 2010-07-22 | Genzyme Corp | MULTI-MORE CONSTRUCTS |
CA2619048A1 (en) | 2005-08-15 | 2007-02-22 | The Regents Of The University Of California | Vegf-activated fas ligands |
KR101866623B1 (en) * | 2005-11-28 | 2018-07-04 | 젠맵 에이/에스 | Recombinant monovalent antibodies and methods for production thereof |
KR20080080651A (en) * | 2005-12-20 | 2008-09-04 | 아라나 테라퓨틱스 리미티드 | Anti-inflammatory dab |
US7846439B2 (en) * | 2006-02-01 | 2010-12-07 | Cephalon Australia Pty Ltd | Domain antibody construct |
CN101074261A (en) * | 2006-04-30 | 2007-11-21 | 北京同为时代生物技术有限公司 | TRAIL receptor I and/or TRAIL receptor 2 specific antibody and its use |
DK2018428T3 (en) * | 2006-05-17 | 2012-05-29 | Uni Klinikum Tuebingen | Anti-inflammatory fusion protein |
DK2101877T3 (en) | 2006-12-28 | 2013-09-23 | Deutsches Krebsforsch | Neutralization of the effect of CD95 to block invasion of glioblastoma cells in vivo |
CN103897063B (en) | 2007-06-01 | 2017-04-12 | 马里兰大学巴尔的摩分校 | Immunoglobulin constant region Fc receptor binding agents |
EP2310409A2 (en) | 2008-06-17 | 2011-04-20 | Apogenix GmbH | Multimeric tnf receptors |
WO2010006772A2 (en) * | 2008-07-14 | 2010-01-21 | Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts | Use of cd95 inhibitors for the treatment of inflammatory disorders |
AR082404A1 (en) | 2010-07-28 | 2012-12-05 | Gliknik Inc | FUSION PROTEINS OF FRAGMENTS OF NATURAL HUMAN PROTEINS TO CREATE COMPOSITIONS OF IMMUNOGLOBULINES FC ORDERLY MULTIMERIZED |
SI2601214T1 (en) | 2010-08-06 | 2018-03-30 | Genzyme Corporation | Vegf antagonist compositions and uses thereof |
EP2655413B1 (en) | 2010-12-23 | 2019-01-16 | F.Hoffmann-La Roche Ag | Polypeptide-polynucleotide-complex and its use in targeted effector moiety delivery |
TWI476001B (en) | 2011-12-26 | 2015-03-11 | Ind Tech Res Inst | Trimeric fc fusion and uses thereof |
CA2899433A1 (en) * | 2012-01-27 | 2013-08-01 | Gliknik Inc. | Fusion proteins comprising igg2 hinge domains |
JP6203838B2 (en) | 2012-06-27 | 2017-09-27 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | Method for selecting and creating tailor-made highly selective and multispecific targeting entities comprising at least two different binding entities and uses thereof |
WO2014001325A1 (en) * | 2012-06-27 | 2014-01-03 | F. Hoffmann-La Roche Ag | Method for making antibody fc-region conjugates comprising at least one binding entity that specifically binds to a target and uses thereof |
CA2876787C (en) | 2012-07-18 | 2021-07-27 | Apogenix Gmbh | Inhibitors of the cd95 signaling pathway for treatment of mds |
ES2674662T3 (en) * | 2012-07-18 | 2018-07-03 | Apogenix Ag | Composition comprising a mixture of CD95-Fc isoforms |
AU2013305885B2 (en) | 2012-08-20 | 2017-12-21 | Gliknik Inc. | Molecules with antigen binding and polyvalent Fc gamma receptor binding activity |
US10189887B2 (en) | 2014-04-17 | 2019-01-29 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Polypeptides and uses thereof for reducing CD95-mediated cell motility |
WO2016118577A1 (en) * | 2015-01-22 | 2016-07-28 | Medimmune, Llc | Thymosin-beta-four fusion proteins |
CA2984350A1 (en) | 2015-05-04 | 2016-11-10 | Apogenix Ag | Single-chain cd40-receptor agonist proteins |
CA3002587A1 (en) | 2015-10-23 | 2017-04-27 | Apogenix Ag | Single-chain light receptor agonist proteins |
AU2016341409B2 (en) | 2015-10-23 | 2021-02-25 | Apogenix Ag | Single-chain CD27-receptor agonist proteins |
CA3026420A1 (en) | 2016-06-07 | 2017-12-14 | Gliknik Inc. | Cysteine-optimized stradomers |
BR112019009484A2 (en) | 2016-12-09 | 2019-07-30 | Gliknik Inc | manufacturing optimization of gl-2045, a multimerizer stradomer |
CA3134144A1 (en) | 2019-03-29 | 2020-10-08 | Myst Therapeutics, Llc | Ex vivo methods for producing a t cell therapeutic and related compositions and methods |
IL293350A (en) | 2019-11-27 | 2022-07-01 | Myst Therapeutics Llc | Method of producing tumor-reactive t cell composition using modulatory agents |
CN115427438A (en) | 2020-02-27 | 2022-12-02 | 迈斯特治疗公司 | Methods for ex vivo enrichment and expansion of tumor-reactive T cells and compositions related thereto |
GB202016058D0 (en) | 2020-10-09 | 2020-11-25 | Ucl Business Ltd | Therapeautic treatment |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999009165A1 (en) * | 1997-08-15 | 1999-02-25 | Idun Pharmaceuticals, Inc. | Trail receptors, nucleic acids encoding the same, and methods of use thereof |
US6072047A (en) * | 1997-02-13 | 2000-06-06 | Immunex Corporation | Receptor that binds trail |
WO2000066156A1 (en) * | 1999-05-04 | 2000-11-09 | Human Genome Sciences, Inc. | Death domain containing receptor 5 |
US6284236B1 (en) * | 1995-06-29 | 2001-09-04 | Immunex Corporation | Cytokine that induces apoptosis |
WO2002097033A2 (en) * | 2001-05-25 | 2002-12-05 | Human Genome Sciences, Inc. | Antibodies that immunospecifically bind to trail receptors |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5116964A (en) | 1989-02-23 | 1992-05-26 | Genentech, Inc. | Hybrid immunoglobulins |
US5830469A (en) * | 1993-10-14 | 1998-11-03 | Immunex Corporation | Fas antagonists and uses thereof |
DE4447484C2 (en) * | 1994-04-08 | 1997-07-17 | Deutsches Krebsforsch | Apoptosis inhibitor |
US6306395B1 (en) | 1996-05-02 | 2001-10-23 | Mochida Pharmaceutical Co., Ltd. | Fas antigen derivatives |
DE69730358T2 (en) * | 1996-10-31 | 2004-12-30 | Mochida Pharmaceutical Co. Ltd. | Fas antagonist FOR PROPHYLAXIS OR THERAPY OF GVHD |
EP1273304B2 (en) | 1997-02-21 | 2009-07-15 | Amgen Inc. | Use of interleukin-15 |
EA200001004A1 (en) | 1998-03-30 | 2001-06-25 | Эли Лилли Энд Компани | THERAPEUTIC APPLICATION OF FLINT MATURE POLYPEPTIDES (mFLINT) OR OPG3, MEMBERS OF THE SUPERFAMILY OF TNF RECEPTORS |
US6472179B2 (en) | 1998-09-25 | 2002-10-29 | Regeneron Pharmaceuticals, Inc. | Receptor based antagonists and methods of making and using |
DE19959049A1 (en) | 1999-12-07 | 2001-06-28 | Deutsches Krebsforsch | Combination of compounds that inhibit the biological effects of TNF-alpha and CD95L |
DE19963859A1 (en) | 1999-12-30 | 2001-07-12 | Apotech Res & Dev Ltd | Bi- or oligomer of a di-, tri-, quattro- or pentamer of recombinant fusion proteins |
CA2438628A1 (en) * | 2001-02-19 | 2002-08-29 | Merck Patent Gesellschaft Mit Beschraenkter Haftung | Artificial proteins with reduced immunogenicity |
US6992174B2 (en) * | 2001-03-30 | 2006-01-31 | Emd Lexigen Research Center Corp. | Reducing the immunogenicity of fusion proteins |
DE10122140A1 (en) | 2001-05-08 | 2002-11-28 | Apotech Res & Dev Ltd | Recombinant fusion proteins and their trimers |
DE10160248A1 (en) | 2001-12-07 | 2003-06-26 | Alexander Cherkasky | New fusion protein, useful for treating e.g. tumors, viral infections and autoimmune disease, comprises an Fc antibody region and at least one other domain and improves the response of antigen-presenting cells |
-
2004
- 2004-03-26 US US10/551,004 patent/US8007813B2/en active Active
- 2004-03-26 PL PL04723552T patent/PL1606318T3/en unknown
- 2004-03-26 WO PCT/EP2004/003239 patent/WO2004085478A2/en active Application Filing
- 2004-03-26 JP JP2006504877A patent/JP4741464B2/en not_active Expired - Lifetime
- 2004-03-26 AU AU2004224123A patent/AU2004224123A1/en not_active Abandoned
- 2004-03-26 PT PT04723552T patent/PT1606318E/en unknown
- 2004-03-26 CA CA002520254A patent/CA2520254A1/en not_active Abandoned
- 2004-03-26 WO PCT/EP2004/003245 patent/WO2004085479A2/en not_active Application Discontinuation
- 2004-03-26 SI SI200431264T patent/SI1606318T1/en unknown
- 2004-03-26 ES ES04723552T patent/ES2327409T3/en not_active Expired - Lifetime
- 2004-03-26 AT AT04723552T patent/ATE438662T1/en active
- 2004-03-26 EP EP04723552A patent/EP1606318B1/en not_active Expired - Lifetime
- 2004-03-26 EP EP04723556A patent/EP1606319A2/en not_active Withdrawn
- 2004-03-26 DE DE602004022390T patent/DE602004022390D1/en not_active Expired - Lifetime
- 2004-03-26 CA CA2520138A patent/CA2520138C/en not_active Expired - Lifetime
- 2004-03-26 JP JP2006504879A patent/JP2007533595A/en active Pending
- 2004-03-26 AU AU2004224122A patent/AU2004224122A1/en not_active Abandoned
- 2004-03-26 DK DK04723552T patent/DK1606318T3/en active
-
2006
- 2006-01-04 HK HK06100143.0A patent/HK1077592A1/en unknown
-
2009
- 2009-10-29 CY CY20091101120T patent/CY1109536T1/en unknown
-
2011
- 2011-08-19 US US13/213,345 patent/US20110305697A1/en not_active Abandoned
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6284236B1 (en) * | 1995-06-29 | 2001-09-04 | Immunex Corporation | Cytokine that induces apoptosis |
US6072047A (en) * | 1997-02-13 | 2000-06-06 | Immunex Corporation | Receptor that binds trail |
WO1999009165A1 (en) * | 1997-08-15 | 1999-02-25 | Idun Pharmaceuticals, Inc. | Trail receptors, nucleic acids encoding the same, and methods of use thereof |
WO2000066156A1 (en) * | 1999-05-04 | 2000-11-09 | Human Genome Sciences, Inc. | Death domain containing receptor 5 |
WO2002097033A2 (en) * | 2001-05-25 | 2002-12-05 | Human Genome Sciences, Inc. | Antibodies that immunospecifically bind to trail receptors |
Non-Patent Citations (4)
Title |
---|
RAFTERY MARTIN J ET AL: "Targeting the function of mature dendritic cells by human cytomegalovirus: A multilayered viral defense strategy" IMMUNITY, vol. 15, no. 6, December 2001 (2001-12), pages 997-1009, XP002296338 ISSN: 1074-7613 cited in the application * |
W.WURZER: "Dissertation: Die Rolle des Transkriptionsfaktors NF-kB in Influenza-A-Virus infizierten Zellen" [Online] 27 June 2003 (2003-06-27) , BAYRISCHE JULIUS-MAXIMILLIANS-UNIVERSITÄT WÜRZBURG XP002296341 Retrieved from the Internet: <URL: http://opus.bibliothek.uni-wuerzburg.de/op us/volltexte/2003/590/pdf/4.Fasung.pdf> [retrieved on 2004-09-10] the whole document * |
WURZER WALTER J ET AL: "Caspase 3 activation is essential for efficient influenza virus propagation." EMBO (EUROPEAN MOLECULAR BIOLOGY ORGANIZATION) JOURNAL, vol. 22, no. 11, 2 June 2003 (2003-06-02), pages 2717-2728, XP002296339 ISSN: 0261-4189 * |
WURZER WALTER J ET AL: "NF-kappaB-dependent induction of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas/FasL is crucial for efficient influenza virus propagation." THE JOURNAL OF BIOLOGICAL CHEMISTRY. 23 JUL 2004, vol. 279, no. 30, 23 July 2004 (2004-07-23), pages 30931-30937, XP002296340 ISSN: 0021-9258 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008528678A (en) * | 2005-02-03 | 2008-07-31 | コーダ セラピューティクス リミテッド | Anti-connexin compounds and their use |
WO2011101031A1 (en) * | 2010-02-19 | 2011-08-25 | Université de Liège | A polynucleotide for use in treatment of influenza a virus induced diseases, encoding modified mx protein, said modified mx protein, and a transgenic animal expressing gene encoding modified mx protein |
US9149025B2 (en) | 2010-02-19 | 2015-10-06 | Universite De Liege | Polynucleotide for use in treatment of influenza A virus induced diseases, encoding modified Mx protein, said modified Mx protein, and a transgenic animal expressing gene encoding modified Mx protein |
Also Published As
Publication number | Publication date |
---|---|
JP2007533595A (en) | 2007-11-22 |
US20110305697A1 (en) | 2011-12-15 |
ES2327409T3 (en) | 2009-10-29 |
US20070269449A1 (en) | 2007-11-22 |
AU2004224122A1 (en) | 2004-10-07 |
CY1109536T1 (en) | 2014-08-13 |
DK1606318T3 (en) | 2009-11-02 |
EP1606319A2 (en) | 2005-12-21 |
AU2004224123A1 (en) | 2004-10-07 |
CA2520138A1 (en) | 2004-10-07 |
EP1606318A2 (en) | 2005-12-21 |
US8007813B2 (en) | 2011-08-30 |
SI1606318T1 (en) | 2009-12-31 |
WO2004085478A2 (en) | 2004-10-07 |
CA2520138C (en) | 2017-05-23 |
ATE438662T1 (en) | 2009-08-15 |
JP2007524365A (en) | 2007-08-30 |
EP1606318B1 (en) | 2009-08-05 |
PL1606318T3 (en) | 2010-01-29 |
WO2004085479A3 (en) | 2004-11-25 |
HK1077592A1 (en) | 2006-02-17 |
JP4741464B2 (en) | 2011-08-03 |
DE602004022390D1 (en) | 2009-09-17 |
PT1606318E (en) | 2009-11-10 |
CA2520254A1 (en) | 2004-10-07 |
WO2004085478A3 (en) | 2005-01-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2004085479A2 (en) | Treatment of viral infections | |
CA2285040C (en) | Death domain containing receptor 5 | |
Jeremias et al. | TRAIL/Apo‐2‐ligand‐induced apoptosis in human T cells | |
US6261801B1 (en) | Nucleic acids encoding tumor necrosis factor receptor 5 | |
JP2001509019A (en) | Binding to death domain containing receptor 4 (DR4: death receptor 4), a member of the TNF-receptor superfamily and TRAIL | |
EP0828751A1 (en) | Human neuropeptide receptor | |
WO2006081311A2 (en) | Compositions and methods for the intracellular disruption of vegf and vegfr-2 by intraceptors | |
JP2011504369A (en) | Improved cytokine design | |
KR20180003538A (en) | Dual signaling protein (DSP) fusion proteins and their use in the treatment of diseases | |
US20120014947A1 (en) | Methods and compositions to reduce liver damage associated with conditions or therapies that affect the immune system | |
WO2017079297A1 (en) | Methods for treatment of cancer | |
WO2002098362A2 (en) | Use of rank antagonists to treat cancer | |
Kasuga et al. | Sensitization of human glioblastomas to tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) by NF‐κB inhibitors | |
Dorstyn et al. | Differential inhibitory effects of CrmA, P35, IAP and three mammalian IAP homologues on apoptosis in NIH3T3 cells following various death stimuli | |
US20030166097A1 (en) | Human tumor necrosis factor receptor | |
Byers et al. | H2-M3 presents a nonformylated viral epitope to CTLs generated in vitro | |
Muneta et al. | Molecular cloning, characterization, and expression of porcine Fas ligand (CD95 Ligand) | |
KR101590959B1 (en) | Recombinant TRAIL Fusion Protein Linked to Hexamerization Domain and Composition for Treating Restenosis Comprising the Same Protein | |
EP0773959A1 (en) | Adrenergic receptor | |
TW202306996A (en) | Bispecific antibodies targeting endothelin receptor type a (eta) and cd3 | |
WO2023094571A1 (en) | Stabilization of ace2 fusion proteins | |
Wang et al. | A Conserved Residue, Tyrosine (Y) 84, in H5N1 In? uenza A Virus NS1 Regulates IFN Signaling Responses to Enhance Viral Infection. | |
EP1788086A1 (en) | Death Domain Containing Receptor 5 | |
Wei et al. | Cancer gene therapy via NKG2D and FAS pathways | |
MCCARTHY et al. | 8 Death signalling by the |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2004224123 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2520254 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2006504879 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004723556 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2004224123 Country of ref document: AU Date of ref document: 20040326 Kind code of ref document: A |
|
WWP | Wipo information: published in national office |
Ref document number: 2004224123 Country of ref document: AU |
|
WWP | Wipo information: published in national office |
Ref document number: 2004723556 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 2004723556 Country of ref document: EP |