Showing papers by "Transgene SA published in 2003"

Recombinant adenovirus shedding after intratumoral gene transfer in lung cancer patients.

Abstract: We conducted two phase 1 trials of direct intratumoral injection of a recombinant E1E3-deleted adenovirus (AdR) encoding either the bacterial enzyme beta-galactosidase (Ad.RSVbetagal) or interleukin 2 (IL2, AdTG5327) into primary nonsmall-cell lung cancers of 21 patients. We report here virus shedding and the duration of virus expression in the tumor after intrabronchial injection of 10(7), 10(8) or 10(9) PFU of adenovirus. The infectious AdR and the viral DNA were detected in PBL, plasma, stool and aerodigestive samples in a dose-dependent manner, since cell cultures and PCRs were found to be positive mainly for samples from patients who received the highest AdR dose (10(9) PFU). We detected beta-galactosidase activity in the tumor biopsy samples of 66% of the patients, seemingly dose related, and only low levels of IL2 mRNA could be detected in tumor biopsy samples. E1 sequences were not detected by PCR in any of the PBL and bronchial samples collected after virus delivery, except in one patient. In this patient, E1 sequences were detected in PBL as well as in tumor biopsy samples collected at days 8, 30 and 60 and were correlated with longer beta-galactosidase expression in tumor samples. PBL tested before and after virus delivery contained both E1 sequences indicating that they did not result from replication-competent adenovirus (RCA) E1 sequences present in the inoculum. In addition, only on the day of the injection was Ad.RSVbetagal also detected in E1-positive PBL, indicating that virus replication in blood was very unlikely.

Technology evaluation: CpG-7909, Coley.

Abstract: Coley Pharmaceutical (formerly CpG ImmunoPharmaceuticals) is developing CpG-7909 (ProMune) for use in the potential treatment of cancer and as a vaccine adjuvant. By April 2000, CpG-7909 had entered phase I/II trials for cancer and in March 2002, Coley initiated a phase I trial in non-Hodgkin's lymphoma in combination with rituximab (Rituxan). By October 2002, CpG-7909 was in phase II trials as a vaccine adjuvant. Cpg-7909 is currently also undergoing phase II trials for melanoma.

Generating MHC Class II+/Ii- phenotype after adenoviral delivery of both an expressible gene for MHC Class II inducer and an antisense Ii-RNA construct in tumor cells.

Abstract: Tumor cells engineered by gene transduction to be MHC Class II+/Ii- are novel APCs capable of presenting endogenous tumor antigen epitopes to activate T helper cells. The MHC Class II+/Ii- tumor cell phenotype is created by transfecting genes for either CIITA or IFN-gamma, and inhibiting induced Ii mRNA by an Ii reverse gene construct (Ii-RGC). Adenoviral vectors are preferred for the delivery of such genes because of high infection efficiency and ubiquity of the adenoviral receptor on many cell types and tumors. Here we show that at 5 MOI (multiplicity of infection), recombinant adenoviruses with CIITA or IFN-gamma genes converted virtually all MC-38 colon adenocarcinoma cells and Renca renal carcinoma cells in culture to MHC Class II+/Ii+ cells. A single recombinant adenovirus with both genes for IFN-gamma and Ii-RGC (rAV/IFN-gamma/Ii-RGC) efficiently induced the MHC Class II+/Ii- phenotype. Injection of tumor nodules with rAV/Ii-RGC and rAV/CIITA/IFN-gamma combined with a suboptimal dose of rAV/IL-2 induced a potent antitumor immune response. The methods are adaptable for producing enhanced genetic vaccines, attenuated virus vaccines (eg, vaccinia), and ex vivo cell-based vaccines (dendritic and tumor cells).

Adenoviral vectors for modulating the cellular activities associated with pods

Abstract: The present invention concerns a method of modulating one or more cellular activities dependent on a POD nuclear structure in a host cell through the action of a molecule of adenoviral origin, wherein said molecule of adenoviral origin is capable of interacting with the cellular function of said POD nuclear structure. In a first aspect, the present invention provides a method, a replication-defective adenoviral vector and a composition intended to reduce or inhibit one or more POD-dependent cellular activities by introducing said adenoviral molecule in the host cell. The invention also relates to the use of such a replication-defective adenoviral vector or molecule to provide a reduction or an inhibition of the antiviral or apoptosis cellular activities as well as to provide a reduction of the toxicity induced by a replication-defective adenovirus vector or to enhance transgene expression driven from said replication­defective adenovirus vector. In a second aspect, the present invention provides a replication-competent adenoviral vector having the native pIX or E4orf3 gene non­functional or deleted, as well as a viral particle, a host cell and a composition comprising such a replication-competent adenoviral vector and a method of treatment using such a replication-competent adenoviral vector. The present invention also concerns a method of enhancing apoptosis in a host cell using such a replication-competent adenoviral vector.

Modified adenoviral fiber with ablated to cellular receptors

Abstract: The present invention concerns a modified adenoviral fiber containing at least one mutation affecting one or more amino acid residue(s) of said adenoviral fiber interacting with at least one glycosaminoglycan and/or sialic acid-containing cellular receptor, as well as a trimer of such a modified adenoviral fiber. The present invention also relates to a DNA fragment, an expression vector encoding said modified adenoviral fiber. The present invention also concerns an adenoviral particle lacking a wild-type fiber and comprising the trimer of modified adenoviral fibers as well as a process for producing such an adenoviral particle. Theto present invention also provides a composition comprising such an adenoviral particle and the therapeutic use thereof.

Expression cassette for persistence of expression of a gene of interest in muscle cells

Abstract: The present invention concerns the use of a nucleic acid fragment comprising a portion of at least 100 contigous nucleotide bases which portion has a sequence the same as, or homologous to a portion of corresponding length of the sequence as set out in SEQ ID NO: 1 starting at nucleotide approximately 1 and ending at nucleotide approximately 16879 or the same as, or homologous to a portion of the corresponding length of the sequence complementary to said SEQ ID NO: 1 within the specified positions, for improving the persistence of transfected cells expressing one or more gene(s) of interest operably linked to said acid nucleic fragment. The invention also relates to an expression cassette for the expression of one or more gene(s) of interest which expression is controlled by one or more control sequence(s) and a nucleic acid fragment as defined above. The present invention also provides a vector containing said expression cassette and a eukaryotic host cell containing said expression cassette or vector as well as a 15 composition comprising said expression cassette, vector or eukaryotic host cell for therapeutic or prophylactic purposes. The present invention is useful for many applications including the the construction of transgenic animal models and somatic gehe therapy, especially for treating or preventing muscle-affecting diseases.

Peptide compositions and their use against HCV

Abstract: The invention relates to novel peptide compositions. In particular, the invention relates to a peptide composition comprising at least two peptides which are selected from among the following peptides: a peptide A having at least the amino acid sequence of SEQ ID N o 1, a peptide B having at least the amino acid sequence of SEQ ID N o 45, a peptide C having at least the amino acid sequence of SEQ ID N o 127, a peptide D having at least the amino acid sequence of SEQ. ID N o 174. The inventive compositions can be used, in particular, in the preparation of active pharmaceutical compositions against the hepatitis C virus.

Combination products for use in antitumoral treatment, comprising an antibody capable of inhibiting the activity of CSF-1

Abstract: Combination product (A) comprises at least one each of: (i) a substance (I) that inhibits expression of colony-stimulating factor-1 (CSF-1) and/or nucleic acid encoding (I), and (ii) a cytotoxic substance (II) and/or nucleic acid that encodes (II). Independent claims are also included for the following: (1) oligonucleotides (ON) of 8-100 nucleotides (nt) that hybridize to the human CSF-1 encoding sequence and inhibit expression of CSF-1; (2) nucleic acid (NA) that includes a sequence encoding ON; and (3) composition containing at least one ON and a pharmaceutical vehicle. ACTIVITY : Cytostatic. MECHANISM OF ACTION : Inhibition of CSF-1 which stimulates mobility and invasiveness of cancer cells and promotes infiltration of monocytes into a tumor and differentiation of them to macrophages. Combination product (A) thus inhibits or delays cell growth and induces cell death, better presentation of antigens and/or better stimulation of immune cells in the host. The oligonucleotide UCUGGAGCAGGUUAAU (S3), directed against residues 284-301 of the CSF-1 coding sequence, was used to transfect NS2TA1 human breast cells that had been transfected with SV40. After 24 hours, the expression of CSF-1 was only 39% of that in untreated controls.