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WO1996040966A1 - Compositions et procedes de traitement de maladies associees a l'interleukine 6 (il-6) - Google Patents

Compositions et procedes de traitement de maladies associees a l'interleukine 6 (il-6) Download PDF

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Publication number
WO1996040966A1
WO1996040966A1 PCT/US1996/008679 US9608679W WO9640966A1 WO 1996040966 A1 WO1996040966 A1 WO 1996040966A1 US 9608679 W US9608679 W US 9608679W WO 9640966 A1 WO9640966 A1 WO 9640966A1
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composition
disorder
cell
cells
culture medium
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PCT/US1996/008679
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Thomas M. Rodgers, Jr.
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Private Biologicals Corporation
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Priority to AU60381/96A priority Critical patent/AU6038196A/en
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    • 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
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4702—Regulators; Modulating activity
    • C07K14/4703—Inhibitors; Suppressors
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P1/00—Preparation of compounds or compositions, not provided for in groups C12P3/00 - C12P39/00, by using microorganisms or enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/91—Cell lines ; Processes using cell lines
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to methods and compositions for treatment of a variety of disorders characterized by elevated IL-6 levels, and is based on materials derived from a transformed B cell line.
  • cytokines have now been purified, cloned and expressed in recombinant hosts. Clinical trials have shown some success, however, there is toxicity in many cases at effective doses and more recent efforts have focused on searches for inhibitors of cytokines. It is therefore an object of the present invention to provide compositions and methods for treatment of disorders associated with elevated levels of cytokines. It is a further object of the present invention to provide compositions for treatment of disorders associated with elevated levels of
  • Transformed B cell lines secrete into a human serum culture medium under controlled conditions an inhibitor of IL-6.
  • the cell culture medium, or purified fractions thereof having IL-6 inhibitory activity can be administered to treat patients having disorders characterized by elevated levels of IL-6, particularly certain types of cancers, autoimmune disorders, pain associated with these disorders, side effects arising from chemotherapy, and wasting or other symptoms of certain viral diseases.
  • the preferred cell line is RPMI 1788, from the American Type Culture Collection, although other B cell lines can also be used as a source of active material.
  • compositions include compositions containing cell secretions produced by B lymphoid cells, induced with a transforming agent such as infection with Epstein Barr vims, and cultured in a human albumin or semm based culture medium or synthetic medium, as obtained by centrifugation or filtration of the cell culture media or in purified form.
  • a transforming agent such as infection with Epstein Barr vims
  • Cells that can be cultured to produce the pharmaceutical compositions are primarily hematopoietic cells, especially human B lymphoid cell lines transformed by Epstein Barr Vims.
  • the most preferred cell line is RPMI 1788, deposited with the American Type Cell Culture Collection under Accession Number CCL 156, which has been previously exposed to Epstein-Barr vims.
  • This cell line is Epstein-Barr vims nucleic antigen-positive, as is about 60% of the human population.
  • the cell culture medium containing the secretions from these cells is referred to herein as "LK-200", although secretions from only one cell line, ATCC CCL 156, is currently being tested clinically.
  • EBV transformed cell lines such as IB4, Raji, which is a Burkett lymphoma cell line, and non- EBV infected B cell lines such as Bjab. These cell lines can be obtained from the ATCC or other sources, for example, Tufts New England Medical Center, Boston, Massachusetts.
  • Inducing Agents Agents which can be used to transform the cells include viruses such as Epstein Barr vims. Inducers, which may be used alone in some cases or in combination with transforming agents, include tumor necrosis factor (TNF), endotoxin, and other agents known to those skilled in the art.
  • TNF tumor necrosis factor
  • the cultured cells are exposed to an amount effective to activate the cells, as determined by cytokine expression, immunoglobulin secretion, and/or other indicators such as proliferation or alteration of cell surface properties or markers.
  • cells are initially exposed to a small amount to "prime” the cells, then to a subsequent dose to elicit greater activation of the cells.
  • the inducing agent is removed from the cell culture medium when the medium is exchanged, either through gradual supplementation or filtration or centrifugation of the cells, followed by decantation of the medium and replacement with fresh medium.
  • the cells are preferably cultured in a medium which can be administered directly to a human patient without eliciting a reaction to the medium.
  • the medium is based on 2% AB human semm, for example, obtained from Bio Whittaker, Inc., Walkersville, MD,or Gibco, Life Technologies, Inc., Grand Island, NY, although albumin can be substituted for the semm immediately prior to harvesting of the cell culture medium.
  • Human serum is placed in Iscove's Modified Dulbecco's Medium (IMDM) containing sodium bicarbonate and 25 mM HEPES in a concentration of 2% L-glutamine.
  • IMDM and L-glutamine can also be obtained from Bio Whittaker.
  • Semm source does have an effect on cytokine levels in the final product, although it is relatively negligible.
  • the level of IL- 8 in Bio Whittaker semm medium after removal of the cells (referred to as "supernatant", regardless of the method of cell removal) was measured as 0.367 ⁇ 0.17 ng IL-8/ml and the level of IL-8 in Gibco serum medium was measured as 0.184 _+ 0.1 ng IL-8/ml; the level of TNF in the Bio Whittaker serum medium was 0.311 ⁇ 0.24 ng TNF/ml and the level of TNF in the Gibco semm medium was 0.179 +. 0.07 ng TNF/ml. Cells will grow and secrete active components in albumin, but only to a limited extent.
  • the blood type of the semm source can elicit a reaction in some patients having a different blood type. Accordingly, although not a problem, it is preferred to utilize a serum source of the same blood type as the patient.
  • Cells are incubated at 37 °C until they reach a minimum density of 1 x 10 6 cells/ml.
  • the pH at the time of harvest is approximately 7.00 _+ 0.15.
  • RPMI 1788 cells obtained from the ATCC are thawed in a 37 °C water bath, suspended at room temperature in 0.2 micron-filtered Iscov's media containing HEPES, obtained from GIBCO BRL Life Technologies, Inc., Gaithersburg, MD, and supplemented with 2% glutamine and 2 to 5% normal human semm (Gibco) or 10 to 25% human albumin (Gibco).
  • Cells are cultured in T75 flasks in an atmosphere of 5% CO 2 at 37 °C until the cell density exceeds 1 x 10 6 cells/ml.
  • the cells can then be removed by centrifugation at 800 x g for 5 minutes or filtration and resuspended in T 150 flasks at a density of 0.2 x 10 6 cells/ml in a total volume of 200 mis of media. Cells are then cultured again until the density reaches 1 x 10 6 cells/rnl and the process is repeated. Cells can then be cultured in 500 ml roller bottles, flushed with 10% CO 2 and sealed, at an initial cell density of 0.2 x 10 6 cells/ml, until the cells reach a density of at least 1 x 10 6 cells/ml.
  • LK200 LK200
  • IB4 peripheral blood cells
  • PBCs peripheral blood cells activated by exposure to a mitogen, PHA, and controls: 2% human semm medium not exposed to cells, 10% fetal calf serum (FCS) medium not exposed to cells, and a T cell line OKT3.
  • FCS fetal calf serum
  • Table 1 demonstrates that the RPMI 1788 cells only weekly express the lambda light chain.
  • RPMI 1788 cells labelled "ATCC" (presumably not propagated in vitro since the initial purchase of the line) are markedly positive for this antigen.
  • the RPMI 1788 line does not express the "naive" CD45 isoform found on the other lines.
  • This line is, however, reactive with the Becton Dickinson HLe-1 mAb.
  • the line may express an isoform containing material encoded by the B alone or the B and C exons. Regardless of the structure of this isoform, the sigmficance of this variant is obscure.
  • (+) and (-) signs indicate 100% and 0% expression respectively.
  • the RPMI 1788 and IB4 cell lines are EBV+LCL.
  • Raji is a Burkitt lymphoma and Bjab a non-EBV-infected B cell line.
  • All mAb used in these FACS analyses were FITC-conjugated except the anti-CD21.
  • the unconjugated anti-CD21 mAb was used with an anti-murine IgG-FITC second step antibody to detect CD21 surface expression.
  • IL-1 beta, TNF, IL-6, IL-10, IL-IRA, soluble IL-1 receptor type II (sIL-IRII), and IL-8 were assayed by RIA.
  • IL-2, IL-4, GM-CSF, and IFN-gamma were assayed by ELISA with kits obtained from Endogen.
  • IL-12 was similarly assayed with a kit from R&D Systems.
  • LK200 and RPMI 1788 supematants contain modest amounts of IL-8 (consistently less than 135 pg/ml) and modest amounts of TNF (less than 250 pg/ml).
  • Supernatant from the Bjab line contains a great deal of IL-10 (920 pg/ml). This is the one B cell line studied that is not EBV-infected.
  • the IB4 line sheds the type II IL-1 receptor (1,100 pg/ml).
  • the Bjab line secretes a modest amount (227 pg/ml) of the IL-IRA.
  • the donor of the PBMC for this experiment was Damien Sorce.
  • 12.5 x 10 6 cells were incubated in 5 ml total volume in 50 ml polypropylene centrifuge tubes which had been previously coated with human albumin (10 ⁇ g/ml x 1 hr).
  • Cells were cultured in RPMI medium supplemented with 2% human AB serum and 4 ⁇ g/ml polymyxin B.
  • the PBMC were vortexed briefly to ensure equilibration of the secreted cytokines throughout the culture medium and then pelleted by centrifugation. The supematants were removed and frozen under sterile conditions for future analysis.
  • IL-IRA soluble IL-1 receptor type II
  • IL-8 soluble IL-1 receptor type II
  • IL-2, IL-4, GM-CSF, and IFN-gamma were assayed by ELISA with kits obtained from Endogen.
  • IL-12 was similarly assayed with a kit from R&D Systems.
  • LK200 The 2% human AB semm used in the generation of LK200 itself induces an abundance of IL-6, IL-8, and IL-IRA, presumably due to FcR signalling.
  • composition not only serves as an inhibitor but is more effective when diluted to lower concentrations, presumably as a result of inhibition or competitive mteractions with other components of the composition.
  • the pharmaceutical composition can consist of the culture medium alone or diluted with deionized water or normal saline (0.15 N NaCl) or other physiological buffer. Care should be taken to avoid changes in pH. The medium should not be diluted until immediately prior to administration to the patient.
  • the cells are removed from the culture medium to yield a supernatant containing the biologically effective molecules.
  • Cells can be removed by centrifugation or filtration.
  • the medium is withdrawn from the roller bottles by decantation, pipetting, filtration or centrifugation, then the medium is placed into sterile syringes. Further processing of the material can be obtained based on separation by molecular weight, chromatography on ion-exchange resins, and other methods known to those skilled in the art, where the active fraction is defined by inhibition of IL-6 activity. Sterilization Sterility can be assured by culturing the cells under standard sterile conditions, with removal of the cell culture medium using aseptic conditions.
  • the cell culture medium can be purified by filtering with a filter not excluding molecules of less than 250,000, or more preferably, not less 150,000 daltons, for example, a 0.25 micron filter.
  • the culture medium may also be sterilizable using gamma irradiation.
  • the supernatant once removed from 37°C temperature and 10% nitrogen atmosphere of the cell culture bottles and separated from the cells, can be maintained at room temperature for at least two to four hours without any loss of activity.
  • the medium should be rapidly frozen (defined as in less than two hours) in liquid nitrogen, on dry ice, or in an ultrafreezer, at a temperature of about -40°C to -80°C.
  • Assays on 45 lots of LK-200 for various cytokines indicate that concentrations are in the nanogram per milliliter range, as shown in Table 2. All lots showed essentially no batch to batch variation. There is some direct correlation with levels of cytokines with human serum concentration in the media.
  • the endotoxin levels in the supematants have consistently measured at or less than 10 pg endotoxin/ml. In general, levels up to 10 ng are acceptable for administration to a patient.
  • Interleukin-6 is a pluripotent cytokine that has an effect on a wide array of different cell types. It is generally recognized as a B-cell growth factor, originally being identified as an inducer of immunoglobulin secretion in the Esptein-Barr Vims (EBV) transformed CESS lymphoblastoid line. Although it is classified as an acute phase protein, its role is multifaceted and remains somewhat cloudy. Clearly, it is an important cytokine thought to be intimately involved in several pathologies.
  • the receptor for IL-6 is gpl3O. This is a transmembrane, transducing receptor which spans the cell membrane and signals the cell once the ligand is bound. Sharing the gpl3O receptor with IL-6 are other cytokines including Leucocyte Inhibitory Factor (LIF), Oncostatin M (OSM), IL-11 and Ciliary Neurotropic Factor (CNTF).
  • LIF Leucocyte Inhibitory Factor
  • OSM Oncostatin M
  • CNTF Ciliary Neurotropic Factor
  • Inhibitors of IL-6 are retinoic acid and some steroids (dexamethasone). Soluble gpl3O at one time had been considered to be inhibitory for IL-6 activity. Binding of IL-6 with soluble gp!3O, however, exacerbates its pathological effects, particularly osteoclast formation. In some diseases, multiple myeloma and Kaposi's sarcoma for example, IL-6 is thought to play an autocrine or paracrine role. In these cases, IL-6 is both generated and then used by the same or adjacent cells, perpetuating the disease.
  • IL-6 has been implicated include the following: Multiple myeloma (mm); Prostate cancer; Ovarian cancer;
  • Critical illness polyneuromyopathy Acute pyelonephritis; Autoimmune hepatitis; Large-cell lymphoma; Alveolar echinococcosis; Endometriosis; Atherosclerosis; Psoriasis; Human Parvovirus infection; Renal cell carcinoma; Preeclampsia; Cholangiocarcinoma; HIV; Acoustic neuromas;
  • Hairy-cell leukemia Necrotizing enterococlitis; Ulcerative colitis;
  • Retinoblastoma Pituitary tumors; Acute pyelonephritis; Thyroid carcinoma; Paraganglioma; Candida albicans infection; Giant cell arteritis;
  • Psoriasis Melanoma; Chronic pancreatitis; Carpal tunnel syndrome;
  • Uterine cancer Pulmonary Large cell carcinoma; Helicobacter pylori infections; Ductal Breast carcinoma; Granulomas of giant cell arteritis;
  • Thyrotoxicosis Osteosarcoma
  • Malignant mesothelioma Malignant mesothelioma
  • Typhoid fever Typhoid fever
  • IgA nephropathy Acute pancreatitis; Fanconi's anemia; Paraneoplastic thrombocytosis; and Cystic fibrosis.
  • Dosages and administration schedules are highly individual and are optimized individually in response to alleviation of clinical symptoms, for example, reduction in tumor mass, relief from bone pain, and other subjective or objective criteria. Cancers and Viral Diseases
  • tumor size can be monitored by standard tumor detection and measurement methods such as CAT scanning (computerized axial tomography), MRI (magnetic resonance imaging), and nuclear medicine scans, as known to those of skill in the art.
  • Progression and involvement of lesions caused by a vims or total anatomic involvement of the disease which are herein used as indicators of the progression of the disease, can be determined by standard methods known in the art for each specific lesion type, depending upon the specific disease, for example, organ function or antibody titers.
  • effectiveness can be measured as a reduction in the intensity and duration of the symptoms of the invention. This can include measurement of pathologic and pathophysiologic activities that are reduced, for example, elevated liver functions, elevated bilirubin levels, enlarged liver size and enlarged spleen.
  • the composition is also effective in reducing side effects of chemotherapy and radiation therapy.
  • Side effects which can be reduced include nausea, vomiting and hair loss. Pain is also reduced in many cases. Pain remission can include remission of pain from a decrease in tumor size or in space-occupying lesions, thus decreasing organ pressure and compression of anatomical structures (i.e., nerves, vessels and other organs), as well as remission in pain not associated with a decrease in tumor size or a decrease in lesions, such as pain in bones and other pain remission that occurs before a significant decrease in tumor size or lesions occurs.
  • anatomical structures i.e., nerves, vessels and other organs
  • Autoimmune Disorders Treatment of Autoimmune Disorders
  • Autoimmunity is described as an immune response mounted against self-components which ultimately results in pathogenic consequences. Diseases which result from autoimmune responses are widespread and varied in clinical presentation.
  • One common factor shared by many of these disease entities is the lack of a known etiologic agent or triggering event for the production of these aberrant responses.
  • Rheumatological illnesses encompass a large number and wide spectmm of different autoimmune diseases, such as rheumatoid arthritis, scleroderma, dermatomyositis, polymyositis, discoid lupus erythematosus, Sjogren's syndrome and systemic lupus erythematosus.
  • Myasthenia Gravis is a disease of unknown etiology, characterized by circulating antibodies to acetylcholine receptors.
  • the disease is manifested by muscle weakness with a predilection for ocular and other cranial muscles. It has a tendency to fluctuate in severity. There are no signs of neurological lesions.
  • the disease is believed to have an immunological basis and anticholinergic antibodies binding to acetylcholine receptors are found in most patients with the disease. Patients may also present with anti-muscle antibodies.
  • the anticholinergic antibodies effectively reduce the number of functional acetylcholine receptors. It is also believed that cellular immune activity against receptors has been found. Patients exhibit generalized weakness that may be fluctuating, most commonly in the use of voluntary muscles.
  • Symptoms such as diplopia, ptosis, and dysphasia are noted. Activity increases weakness of affected muscles. In some cases, efficacy will be demonstrated by reduction in autoantibody levels, in other cases by a decrease in the severity of symptoms. For example, efficacy can be demonstrated by an improvement in large muscle and proximal muscle dysfunction, a reduction in anti-acetylcholine activity, reduction in anti- smooth muscle antibody levels, and improvement in swallowing dysfunctions and dysphasia. Dosages The general method of administration and dose schedule for LK-
  • LK-200 is as follows. Frozen LK-200 is thawed in less than two hours, without excessive heating or mechanical agitation. 50 cc of the LK-200 is then mixed with 50 to 100 cc of normal saline. In some instances, depending upon disease or response, 100 to 200 cc of LK-200 may be mixed with 50 to 100 cc of sterile normal saline. In general, 50 cc mixed with 50 to 100 cc of Sterile Normal Saline is administered once daily for the first 10 to 14 days and then on a three times a week schedule. In some circumstances, up to 200 cc of LK-200 mixed with 50 to 100 cc sterile normal saline is administered four times a day. The mixture is infused intravenously over a 5 to 45 minute period, depending upon " the total volume to be administered. A slower rate is sometimes used if there is a possibility of cardiac decompensation in a patient.
  • the intravenous administration can be accomplished peripherally through normal intravenous injection.
  • patients have specialized ports, such as a Hieman Catheter, which can be used for infusion. This includes certain sub-clavian catheters which are used for chemotherapy and or hyperalimentation or other accepted uses of these catheters.
  • the LK-200 can also be administered via a direct intra-arterial infusion on a selective basis, or via intra-peritoneal infusion.
  • Portable infusion pumps may be preferred in some cases.
  • Dosages can be varied from one to four doses daily or decreased to one every other day or two or three times a week. Dosages typically will be equivalent to between 0.1 and 100 cc/day, averaging about 10 to 50 cc administered once or twice a day or every other day.
  • dosages as provided above are based on administration of the cell culture medium. In the event that the purified fractions are used, the dosage will be adjusted accordingly.
  • Example 1 Treatment of Cancer Patients.
  • Day 1 through Day 7 One daily dose of 10 - 50 ml LK 200 was administered intravenously in 100 ml normal saline, over 15 to 30 minutes.
  • LK 200 Upon administration of the first dose of LK 200, patients experienced the following immediate effects, i.e., within about 24 - 48 hours, in addition to the immediate tumor shrinkage detailed in Table 4: remission of pain; increase in appetite; increase in energy, halting of wasting; increase in quality of sleep.
  • Table 4 provides data from patients treated with LK 200, detailing the regression of specific tumors or lesions associated with the listed disease. Tumors and lesions were measured by CAT scan, MRI and visual inspection.
  • Prior record immunocompromised male due to HIV; CD4 counts less than 25; prior treatment included interferon 3 times per week for 1 year, with no regression of the multiple lesions.
  • Example 2 Treatment of patients with psoriasis. Psoriatic keratinocytes (skin cells) produce and respond to IL-6.
  • a second patient with psoriasis associated with malignant myeloma was treated with LK-200.
  • the psoriasis had been unresponsive to traditional medical treatment.
  • Example 3 Treatment of patient with Rheumatoid Arthritis.
  • LK-200 suppresses the generation of inflammatory cytokines.
  • the sedimentation rate in other patients being treated with LK-200 have also fallen dramatically regardless of the type of tumor or underlying immunologic disease.
  • the sed rate (ESR) is a cmde index of the severity of an ongoing inflammatory disorder. It is largely determined by the plasma level of fibrinogen, a coagulation protein produced in the liver.
  • the production of fibrinogen is regulated by IL-6.
  • a precipitous decline in the ESR could therefore be due to the suppression of IL-6 production or to interference with its biologic effects.
  • Rheumatoid Arthritis who was refractory to all forms of conventional therapy including gold treatments and methotrexate therapy was treated with LK-200.
  • the patient had a sed rate of 60 at the start of therapy.
  • LK-200 was administered for two weeks. After two weeks of therapy, the patient's sed rate had returned almost to normal at around 15-20. She had no further pain in her hands and she was able to resume household chores.
  • Example 4 Treatment of female patient with myasthenia gravis.
  • the patient is a thirteen year old white female with an established diagnosis of Myasthenia Gravis. She was in an extremely weakened condition, in a wheel chair, unable to lift her head, and unable to easily move any of her large peripheral muscle groups. She had a strongly positive Hess test for ocular paralysis. She had extreme ptosis, with moderate diplopia. The patient had a peak flow of 325 cc prior to the start of therapy. She was maintained on Mestinon 60 milligrams every two hours during the day and 180 milligrams at bedtime.
  • Method Sterile thawed LK-200 was administered i.v. to the patient over a period of 20 to 45 minutes. 50 cc of LK-200 was mixed with in 50 cc of sterile normal saline and prepared for infusion by peripheral intravenous injection. The IV solution was administered to the patient daily on Monday through Friday for two weeks.
  • acetylcholine antibodies and anti-smooth muscle antibodies further demonstrate efficacy. After ten days of treatment with LK-200, the level of acetylcholine receptor antibodies was 3.9 nmols/L. After an additional month of treatment the level had decreased to 3.0 nmols/L.

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Abstract

Des lignées de lymphocytes B transformées sécrètent dans un milieu de culture à base de sérum humain, et dans des conditions régulées, un inhibiteur d'IL-6. Il est possible d'administrer ce milieu de culture cellulaire ou des fractions purifiées de celui-ci, présentant une action inhibitrice par rapport à IL-6, à des patients afin de traiter des affections caractérisées par des niveaux élevés d'IL-6, notamment certains types de cancer, des affections auto-immunes, des douleurs associées à ces troubles, des effets secondaires découlant d'une chimiothérapie, le dépérissement ou d'autres symptômes de certaines maladies d'origine virale. La lignée cellulaire préférée est la lignée RPMI 188, de l'American Type Cell Culture Collection, encore que l'on puisse également faire appel à d'autres lignées de lymphocytes B comme source de substance active. Des exemples démontrent l'efficacité de telles lignées dans le traitement de patients atteints de cancer ainsi que dans le traitement d'affections auto-immunes.
PCT/US1996/008679 1995-06-07 1996-06-04 Compositions et procedes de traitement de maladies associees a l'interleukine 6 (il-6) WO1996040966A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU754006B2 (en) * 1998-03-17 2002-10-31 Chugai Seiyaku Kabushiki Kaisha Preventives or remedies for inflammatory intestinal diseases containing as the active ingredient IL-6 antagonists
RU2392967C2 (ru) * 2003-10-17 2010-06-27 Тугаи Сейяку Кабусики Кайся Терапевтический агент для мезотелиомы
US8440196B1 (en) 1998-08-24 2013-05-14 Chugai Seiyaku Kabushiki Kaisha Treatment for pancreatitis using IL-6 receptor antagonist antibodies
RU2666942C1 (ru) * 2017-08-14 2018-09-13 федеральное государственное бюджетное учреждение "Национальный медицинский исследовательский центр имени В.А. Алмазова" Министерства здравоохранения Российской Федерации (ФГБУ "НМИЦ им. В.А. Алмазова" Минздрава России) Способ лечения полинейромиопатии критических состояний у реанимационных больных

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EP0696594A1 (fr) * 1994-08-10 1996-02-14 Bayer Corporation Inhibiteur d'interleukine-6 humaine

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EP0448181A2 (fr) * 1990-03-23 1991-09-25 Yamanouchi Europe B.V. Compositions inhibitrices de l'interleukine-6
EP0696594A1 (fr) * 1994-08-10 1996-02-14 Bayer Corporation Inhibiteur d'interleukine-6 humaine

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU754006B2 (en) * 1998-03-17 2002-10-31 Chugai Seiyaku Kabushiki Kaisha Preventives or remedies for inflammatory intestinal diseases containing as the active ingredient IL-6 antagonists
KR100407811B1 (ko) * 1998-03-17 2003-12-01 츄가이 세이야꾸 가부시키가이샤 인터루킨-6 안타고니스트를 유효성분으로서 함유하는 염증성 장질환의 예방 또는 치료제
US6723319B1 (en) 1998-03-17 2004-04-20 Chugai Seiyaku Kabushiki Kaisha Method of treating inflammatory intestinal diseases containing as the ingredient IL-6 receptors antibodies
US7824674B2 (en) 1998-03-17 2010-11-02 Chugai Seiyaku Kabushiki Kaisha Preventive or therapeutic agent for inflammatory bowel disease comprising IL-6 antagonist as an active ingredient
US8440196B1 (en) 1998-08-24 2013-05-14 Chugai Seiyaku Kabushiki Kaisha Treatment for pancreatitis using IL-6 receptor antagonist antibodies
RU2392967C2 (ru) * 2003-10-17 2010-06-27 Тугаи Сейяку Кабусики Кайся Терапевтический агент для мезотелиомы
AU2004281139B2 (en) * 2003-10-17 2011-01-20 Chugai Seiyaku Kabushiki Kaisha Therapeutic agent for mesothelioma
US8802092B2 (en) 2003-10-17 2014-08-12 Chugai Seiyaku Kabushiki Kaisha Mesothelioma therapeutic agent
RU2666942C1 (ru) * 2017-08-14 2018-09-13 федеральное государственное бюджетное учреждение "Национальный медицинский исследовательский центр имени В.А. Алмазова" Министерства здравоохранения Российской Федерации (ФГБУ "НМИЦ им. В.А. Алмазова" Минздрава России) Способ лечения полинейромиопатии критических состояний у реанимационных больных

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