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WO1996006942A1 - Lymphocytes t modifies genetiquement - Google Patents

Lymphocytes t modifies genetiquement Download PDF

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Publication number
WO1996006942A1
WO1996006942A1 PCT/EP1995/003410 EP9503410W WO9606942A1 WO 1996006942 A1 WO1996006942 A1 WO 1996006942A1 EP 9503410 W EP9503410 W EP 9503410W WO 9606942 A1 WO9606942 A1 WO 9606942A1
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Prior art keywords
cell according
cell
epitope
cells
poly
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PCT/EP1995/003410
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German (de)
English (en)
Inventor
Hartmut Wekerle
Hans Thoenen
Rainer Kramer
Yiping Zhang
Original Assignee
MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V.
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Priority to EP95931225A priority Critical patent/EP0782627A1/fr
Priority to JP8508497A priority patent/JPH10505235A/ja
Priority to AU34745/95A priority patent/AU3474595A/en
Publication of WO1996006942A1 publication Critical patent/WO1996006942A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/185—Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • 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
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/48—Nerve growth factor [NGF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy

Definitions

  • the invention relates to genetically modified mature T cells with autoreactive receptors which carry at least one externally introduced gene in their genome which is capable of expressing a (poly) peptide.
  • the invention further relates to medicaments which contain such T cells.
  • the object of the invention was therefore to provide a vehicle with which a biologically active molecule can be transported to a desired target molecule or target tissue and only interacts with it.
  • This problem is solved by providing a T cell with the features of claim 1.
  • the invention thus relates to a genetically modified, mature T cell with the following properties:
  • T cell or its precursor has been modified using molecular biological techniques.
  • Suitable molecular biological techniques such as vector constructions, transformations or transfections or (inducible) expressions are described, for example, in Sambrook et al. , "Molecular Cloning", Cold Spring Harbor Laboratory, Cold Spring Harbor (1989).
  • autoreactive means that the T cell receptor bind an autoantigen presented by an MHC molecule to a suitable cell.
  • the term “externally introduced gene which is normally not expressed in mature T cells” means that the gene coding for the (poly) peptide, which may be of homologous or heterologous origin, does not exist in vivo in mature T cells is expressed and the expression is only achieved through the molecular biological manipulations.
  • the externally introduced gene can, for example, be under the control of its own regulatory elements. According to the invention, one or more of these genes on one or more vectors may have been introduced into the T cells simultaneously or in succession.
  • a vehicle for the first time which can transport and deliver a heterologous protein directly and specifically to a target sequence or target location, for example in the nervous system.
  • This specificity is achieved by the specificity of the T-cell receptor, which recognizes a certain autoantigen presented by an MHC molecule. Since it is known that If the reactivity pattern of a T cell receptor is highly specific, the T cell receptor and thus the molecule to be transported do not interact with other undesired molecules in the body of a patient. In the area of the nervous system there is another peculiarity that can be used for the proposed therapeutic route.
  • the MHC antigens are induced in a large number of pathological changes. This relates in particular to degenerative and inflammatory processes, in the course of which glial cells of the nerve tissue acquire the ability to present antigens.
  • diseases such as Parkinson’s disease or Alzheimer are examples.
  • the brain-reactive T lymphocytes according to the invention preferably detect such altered brain areas, tissue areas where the therapeutic agents are particularly needed.
  • a pool of mature T cells is removed from a patient for producing the T cell according to the invention by customary methods and immediately selected for uniform properties, in particular with regard to the receptor specificity.
  • the T cell according to the invention is usually reapplied to the patient from whom the T cells were originally removed in order to avoid histocompatibility problems.
  • neurotrophic molecules or anti-inflammatory factors can, for example, be brought to specific target locations and used there to prevent harmful side effects. This can take place, for example, in that the neurotrophic factors act on a target cell and there a cascade is desired. biochemical or metabolic events. An example of this is that in Parkinson's patients the remaining substantia nigra is kept alive and thus further cell loss is avoided.
  • the expressed (poly) peptide is exposed or secreted on the surface.
  • the expression of the (poly) peptide on the surface occurs when the (poly) peptide has a membrane anchoring sequence. If the (poly) peptide does not naturally contain such a sequence, it can be added genetically using conventional methods without any problems.
  • the surface expression of the (poly) peptide is particularly desirable if an interaction is only to take place with the cell to which the T cell has docked via its receptor.
  • secretion of the (poly) peptide is desirable if its effect is not to be restricted to the docked cell itself.
  • secreted (poly) peptides are antibodies or neurotrophic, immunomodulating or growth-regulating substances. If these (poly) peptides naturally do not have any signal sequences necessary for export, the person skilled in the art can easily attach them by genetic engineering.
  • the expressed (poly) peptide inhibits or activates the expression of endogenous proteins, the inhibition or activation leading to a change in the pattern on the surface of endogenous (poly) peptides or secreted proteins / Peptides.
  • the (poly) peptide has a trigger function in order to change the expression pattern of the cell.
  • This change in the expression pattern in turn exerts a desired effect on a target molecule or a target cell, for example via the Expression or the inhibition of the expression of a neurotrophic, immunomodulating or growth-regulating molecule or a surface molecule is achieved.
  • An example of this embodiment are immunomodulators which regulate the expression of the MHC molecules down in the brain.
  • its receptor is directed against an epitope of the nervous system.
  • the epitope is an epitope of the central nervous system.
  • examples include proteins that occur specifically in certain brain areas or defined cell types. This is the case for transmitter-specific enzymes (tyrosine hydroxylase), but also possibly for the pigment of the substantia nigra (Parkinson) or certain transmitter receptors.
  • Transient-specific enzymes tyrosine hydroxylase
  • Parkinsoninson the pigment of the substantia nigra
  • Regionally specific receptors and neuropeptides e.g. Galanin to call CGRP.
  • the epitope is an epitope of the peripheral nervous system.
  • Another particularly preferred embodiment of the invention relates to a T cell, the receptor of which is directed against an epitope of the myelin protein P2 or against S100.
  • the epitope is an epitope of a state-specific protein, for example amyloid precursor protein (APP), a tissue-specific protein, a receptor protein, for example regionally specific GABA, glutanate or glycine Receptors, a cytoskeleton protein or a transmitter synthesis enzyme, for example tyrosine hydroxylase.
  • a state-specific protein for example amyloid precursor protein (APP), a tissue-specific protein, a receptor protein, for example regionally specific GABA, glutanate or glycine Receptors, a cytoskeleton protein or a transmitter synthesis enzyme, for example tyrosine hydroxylase.
  • neurotrophic factor is understood to mean mediators who control the survival, growth and differentiation of neuronal cells. Neurotrophins also have the ability to protect neurons against various types of damage and to restore impaired functions.
  • the neurotrophic factor belongs to the NGF gene family (neurotrophins) and is, for example, NGF, BDNF, NT-3, NT-4/5, NT-6 or other neurotrophic factors, such as FGF , GDNF or CNTF.
  • NGF neurotrophins
  • BDNF neurotrophin-derived neurotrophic factor
  • NT-3 neurotrophic factor
  • NT-4/5 neurotrophic factors
  • NT-6 neurotrophic factor
  • NT-6 neurotrophic factor
  • the transport of these neurotrophic factors, alone or in combination, by means of inventive autoreactive T cells directed against an epitope of the nervous system enables e.g. the study and application of therapeutic options for degenerative, traumatic, metabolic or myelodegenerative diseases of the nervous system, such as Alzheimer's disease, Parkinson's see disease, tumors, degenerative diseases, autoimmune diseases, infections, metabolic or traumatic diseases.
  • a further preferred embodiment of the invention relates to a T cell which has the CD4 + CD8 ⁇ phenotype.
  • T-helper cells will primarily be used as vehicles when CD4 + T lymphocytes occur in two subclasses (Thl and Th2), which differ in the spectrum of the cytokines produced and thus also differ Have functions.
  • Thl cells produce especially interferon-gamma and tumor necrosis factor (- ⁇ and -ß).
  • Th2 cells specialize in IL-4, IL-5 and IL-10.
  • Thl cells would mainly be used in degenerative processes, but also in tumors (they induce MHC antigens), while Th2 cells are inflammatory have a dampening effect and would be helpful for autoimmune diseases (e.g. MS etc.).
  • CD8 + lymphocytes are mostly highly effective killer lymphocytes which are used in the field of tumor and virus defense can.
  • the externally introduced gene is under the control of retroviral regulatory elements.
  • retroviral regulatory elements is understood here to mean any regulatory element for the expression of genes which has been isolated from retroviruses or which has been derived from such elements. Examples of such regulatory elements are retroviral promoters or enhancers.
  • the use of retroviral regulatory elements has the particular advantage that the genes under their control are only expressed when the T cells are activated. In other words, the (poly) peptide is only expressed when the T cells are activated by interaction of the receptor with the antigen. In this way, tissue-specific expression and controllability of the expression of the (poly) peptide is achieved by activating the T cell at the target site.
  • the regulatory elements can be adapted to the respective requirements.
  • a further preferred embodiment of the invention relates to a T cell in which the externally introduced gene is under the control of an inducible promoter.
  • the use of an inducible promoter also has the advantage that the expression of the (poly) peptide in the T cell can be controlled and can therefore be tissue-specific. Inducible promoters are widely known in the art.
  • the externally introduced gene is under the control of T cell-specific regulatory elements.
  • a more finely tuned activation of the externally introduced gene (transgene) could be achieved, possibly also a longer (permanent) expression of the transgene.
  • the externally introduced gene is recombinant components of the genome of a lytic / lysogenic T cell-specific virus, which can lyse the T cell after the receptor has been attached to the target epitope .
  • This embodiment also serves for the defined release of the (poly) peptide at its destination.
  • the function of the secretion from the cell in the embodiments of the invention discussed above is enhanced by the apoptosis of the T-lymphocytes according to the invention, which are promoted by the special microenvironment of the target tissue.
  • the invention further relates to a medicament which contains a T cell according to the invention in combination with a pharmaceutically acceptable carrier.
  • the medicaments according to the invention can be used for all diseases whose treatment has a local interaction of the (poly) peptide or a combination of (poly) peptides with one or more target molecules. It is conceivable that such a drug contains one or more different T cells according to the invention, which in turn express one or more of the externally introduced (poly) peptides.
  • the pharmaceuticals according to the invention are suitable, for example, for the treatment of regenerative or inflammatory diseases.
  • the invention relates to the use of an inventive T-cell for the treatment of degenerative Erkran ⁇ effects such as ALS (amyotrophic lateral sclerosis), Alzheimer's disease, pressures Parkinson 1 shear's disease, multiple sclerosis, trauma, infections, autoimmune diseases, immunosuppression, vascular insults, tumors, or acute edema.
  • ALS amotrophic lateral sclerosis
  • Alzheimer's disease amyotrophic lateral sclerosis
  • pressures Parkinson 1 shear's disease CAD
  • multiple sclerosis trauma, infections, autoimmune diseases, immunosuppression, vascular insults, tumors, or acute edema.
  • FIG. 1A retroviral NGF construct which has been used for transduction of R4 lymphocytes
  • B NGF production by R4 T cells after retroviral
  • C NGF expression in EAN (experimental autoimmune neuritis) in filtrates by transduced T-lymphocytes (in situ hybridization). The animals were sacrificed 14 days after the injection of 2.5 ⁇ 10 6 NGF-transduced (upper and lower diagram) or wild-type R4 lymphocytes (middle diagram) into the tail vein of ether-anesthetized adult Lewis rats ;
  • FIG. 2 Clinical results and weight changes in rats in which EAN has been induced. The animals were examined daily for clinical disease symptoms (FIG. 2A) and change in weight (FIG. 2A);
  • Fig. 4 Cellular composition of EAN infiltrates caused by NGF-transduced or control T cell lines in the presence or absence of exogenous NGF: Immunohistochemical staining of W3 / 13-positive T lymphocytes (left row) or EDI-positive macrophages (right row) in the sciatic nerve, positive cells. Positive cells are cells which bind the antibody, ie which express the marker antigen on the surface.
  • Treatment groups a, only wild-type R4 cells __. ⁇ , b, NGF-transduced R4 cells, c) and d) Wilc, -p-R4 cells in combination with the administration of either BSA (c) or NGF protein (d), e, distribution of ET1- and W3-13 positive cells a.. ⁇ s a) to d) shown as a bar graph, including the values for recipients of sham-translated R4 cells (immunocytochemistry not shown). * Statistical significance was examined by the Student t test p ⁇ 0.00001.
  • the neuritogenic, P2 protein-specific R4 cell line was used as a cellular vehicle of NGF in the peripheral nervous system.
  • R4 lymphocytes induce demyelizing autoimmune inflammation (EAN), which is limited only to the peripheral nervous system (PNS) (Linington et al., J. Immunol. 133 (1984), 1946-1950).
  • PNS peripheral nervous system
  • the lesion is characterized by a strong infiltration of mononuclear cells, followed by extensive destruction of the myelin sheath (Izumo, S. et al., Lab. Invest. 53 (1985), 209-218).
  • the time course and the extent of the pathogenic reactions are highly predictable.
  • the clinical manifestations of this disease develop very quickly four days after the induction of the T cells and are caused by one markedly reduced nerve conduction within a few hours (Hier, K. et al., Ann. Neurol. 19 (1986), 44-49).
  • R4 lymphocytes were transduced with a replication-deficient, ecotrophic recombinant retrovirus, which encodes the cDNA of mouse NGF (FIG. 1 a).
  • a replication-deficient, ecotrophic recombinant retrovirus which encodes the cDNA of mouse NGF (FIG. 1 a).
  • an 882 bp Sphl / PstI fragment of the mouse NGF cDNA J. Scott et al., Nature 302 (1983), 538-540
  • was first under the control of the viral promoter in the 5'-LTR of the 5.8 kb vector pLXSN D. Miller et al., Bio Technique 7, (1989) 980-990.
  • Functional splice donor (SD) and splice acceptor (SA sites) are located upstream of the NGF cDNA.
  • GP + E-86 packaging cell line (D. Markowitz et al., J. Virol. 62 (1988) pp. 1120-1124) was transfected by calcium phosphate coprecipitation. The retrovirus-containing supernatant was collected after 48 hours and used to infect a GP + E-86 culture treated with tunicamycin (100 ng / ml 16 hours).
  • G418 (1 mg / ml) resistant clones were subcloned after 12 days and tested for the production of infectious retroviral particles, the number of G418-resistant NIH 3T3 fibroblasts being determined.
  • the titers of the individual packaging clones were in the range from 2 to 6 x 10 plaque-forming units (pfu) per ml.
  • R4 lymphocytes were activated for 48 hours in the presence of native bovine myelin P2 protein (20 ⁇ g / ml) and thymus cells (1x10 cells / ml irradiated at 2000 R) as a source of antigen-presenting cells. These stimulated lymphoblasts were treated with RPMI 1640 containing 5% fetal calf serum, 15% T cell growth factor (Supernatant from ConA-activated mouse spleen cells) supplemented with 80% retrovirus ( 6 ⁇ 10 6 pfu / ml) and 8 ⁇ g / ml polypene transduced.
  • Virus-containing supernatant was removed by repeated washing and transduced R4 lymphocytes were resuspended in RPMI 1640 medium and grown in an atmosphere containing 5% CO2 at 37 ° C.
  • Conditioned media of 10 wild-type (R4) -, NGF-retrovirus transduced (R4NGF) - or sham-transfected (retrovirus, which does not encode NGF; R4mock) R4-lymphocytes were found at NGF concentration (pg / ml) 12 hours after the Transfection tested by an immunoassay testing two binding sites (S. Korsching et al., Proc Natl. Acad. Sci. USA 80 (1983) 3513-3516).
  • the transduction itself did not change the antigen specificity or the proliferative activity of the R4 cells; the Thl-like secretion pattern on cytokines with a strong production of 11-2 and interferon-7 also remained unchanged (results not shown).
  • the transduced R4 lymphocytes infiltrated the peripheral nervous system to the same extent as wild-type or sham-transfected R4 cells (FIG. 4). 14 days after the travenous injection of NGF-transduced R4 cells could be shown by in situ hybridization (Fig. lc) that these genetically modified lymphocytes still strongly express NGF-mRNA in vivo in the peripheral nervous system.
  • Fig. lc in situ hybridization
  • 2,5 ⁇ 10 6 -stimulated wild-type (R4), NGF-transduced (R4NGF) or sham-transfected (R4mock) -R4 lymphocytes into the tail vein were ether-anesthetized Lewis rats in a total volume of 1 ml injected on day 0.
  • the animals were sacrificed 14 days after the injection of 2.5x10 R3-T lymphocytes and perfused with 4% paraformaldehyde containing 0.5% glutardialdehyde in 0.1 M phosphate-buffered saline, using the same fixative overnight at 4 ° C immersion fixed and then embedded in Epon by conventional methods.
  • 1 ⁇ m sections were made and stained with 0.1% toluidine blue to estimate the extent of demyelination; the unit of measure here is 2.5 ⁇ m.
  • Ultra-thin sections were made and prepared for electron microscopy, as described by J. Gehrmann et al. Lab. Invest. 67 (1992) 100-113; one unit on the scale is 1 ⁇ m.
  • Bovine serum albumin or NGF was administered to ether-anesthetized Lewis rats by implantation of a sponge gel cushion (spongostan) containing either 125 ⁇ g NGF (2.5 S) or 250 ⁇ g BSA (Sigma, Cohn fraction V) in 50 ⁇ l 0.9% Na ⁇ trium chloride contained.
  • the administration took place in the vicinity of the left or right sciatic nerve in the sub-gluteal region of the same rat 24 hours before the injection of 2.5 ⁇ 10 6 wild-type R4 cells.
  • cryostat sections (10 ⁇ m) of the sciatic nerve preparations were carried out under stringent conditions either with single-stranded s 35-labeled antisense (upper and middle diagram) or more meaning-oriented (lower diagram) ) NGF-specific cDNA probes hybridized by reverse transcription from sense or antisense NGF cRNA according to customary methods (E. Castren et al., Proc. Natl. Acad. Sci. USA 89 ( 1992) 9444-9448).
  • the morphological changes caused by NGF-transfected R4 cells differed significantly from typical EAN, which was brought about by non- or sham-transfected R4 cells (FIG. 3).
  • the demyelination of the sciatic nerve axons V / L r 14 days after the transfer of NGF-synthesizing R4 lymphocytes was drastically reduced (FIG. 3c), whereas that with the wild type (FIG. 3a) or with the sham-transfected R4 cells (FIG 3b) treated animals showed the typical changes in peripheral myelin sheaths.
  • NGF protein by implantation of a sponge gel cushion in vivo showed the same reduction in macrophage invasion as the NGF-producing R4 cells (FIG. 4d).
  • the implantation of a sponge gel cushion containing BSA on the contralateral side (FIG. 4c) had no influence on the typical macrophage recruitment in EAN induced by the transfer of wild type R4 cells.
  • the number of W3 / 13 positive cells on the differently treated sides of the rats were the same (FIGS. 4c, d).

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Abstract

L'invention concerne des lymphocytes T matures modifiés génétiquement, contenant des récepteurs autoréactifs et comportant dans leur génome au moins un gène, introduit de l'extérieur, pouvant exprimer un (poly)peptide. L'invention concerne en outre des médicaments contenant ces lymphocytes T.
PCT/EP1995/003410 1994-08-31 1995-08-30 Lymphocytes t modifies genetiquement WO1996006942A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP95931225A EP0782627A1 (fr) 1994-08-31 1995-08-30 Lymphocytes t modifies genetiquement
JP8508497A JPH10505235A (ja) 1994-08-31 1995-08-30 遺伝学的に改変されたｔ細胞
AU34745/95A AU3474595A (en) 1994-08-31 1995-08-30 Genetically altered t-cells

Applications Claiming Priority (3)

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DE4431011 1994-08-31
DEP4431011.0 1994-08-31
US60/001,547 1995-07-27

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996034970A1 (fr) * 1995-05-04 1996-11-07 United States Of America, Represented By The Secretary Of The Navy Procedes ameliores de transfection des lymphocytes t
US6692964B1 (en) 1995-05-04 2004-02-17 The United States Of America As Represented By The Secretary Of The Navy Methods for transfecting T cells
US7067318B2 (en) 1995-06-07 2006-06-27 The Regents Of The University Of Michigan Methods for transfecting T cells

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991005037A1 (fr) * 1989-09-28 1991-04-18 Haberman Allan B Lymphocytes t adherant a une proteine matricielle extracellulaire
WO1992005794A1 (fr) * 1990-09-28 1992-04-16 Immunex Corporation Methode servant a produire des lymphocytes t cytotoxiques th-independants

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991005037A1 (fr) * 1989-09-28 1991-04-18 Haberman Allan B Lymphocytes t adherant a une proteine matricielle extracellulaire
WO1992005794A1 (fr) * 1990-09-28 1992-04-16 Immunex Corporation Methode servant a produire des lymphocytes t cytotoxiques th-independants

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KRAMER ET AL: "SELF-SPECIFIC T LYMPHOCYTE LINES AS VEHICLES FOR GENE THERAPY:MYELIN SPECIFIC T CELLS CARRYING EXOGENOUS NERVE GROWTH FACTOR GENE", JOURNAL OF CELLULAR BIOCHEMISTRY,SUPPLEMENT 17E, pages 215 *
MAVILIO ET AL: "PERIPHERAL BLOOD LYMPHOCYTES AS TARGET CELLS OF RETROVIRAL VECTOR-MEDIATED GENE TRANSFER", BLOOD, vol. 83, no. 7, 1 April 1994 (1994-04-01), pages 1988 - 1997 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996034970A1 (fr) * 1995-05-04 1996-11-07 United States Of America, Represented By The Secretary Of The Navy Procedes ameliores de transfection des lymphocytes t
US6692964B1 (en) 1995-05-04 2004-02-17 The United States Of America As Represented By The Secretary Of The Navy Methods for transfecting T cells
US7172869B2 (en) 1995-05-04 2007-02-06 The United States Of America As Represented By The Secretary Of The Navy Methods for transfecting T cells
US7067318B2 (en) 1995-06-07 2006-06-27 The Regents Of The University Of Michigan Methods for transfecting T cells

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JPH10505235A (ja) 1998-05-26
CA2198891A1 (fr) 1996-03-07
AU3474595A (en) 1996-03-22
EP0782627A1 (fr) 1997-07-09

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