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WO1993011793A1 - Utilisation de la combinaison du facteur de necrose anti-tumeur et de l'interleukine-6 dans le traitement du choc septique - Google Patents

Utilisation de la combinaison du facteur de necrose anti-tumeur et de l'interleukine-6 dans le traitement du choc septique Download PDF

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Publication number
WO1993011793A1
WO1993011793A1 PCT/US1992/010596 US9210596W WO9311793A1 WO 1993011793 A1 WO1993011793 A1 WO 1993011793A1 US 9210596 W US9210596 W US 9210596W WO 9311793 A1 WO9311793 A1 WO 9311793A1
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WIPO (PCT)
Prior art keywords
septic shock
tnf antibody
tnf
antibody
combination
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PCT/US1992/010596
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English (en)
Inventor
Beverly E. Barton
James V. Jackson
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Schering Corporation
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Publication of WO1993011793A1 publication Critical patent/WO1993011793A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines

Definitions

  • TNF Tumor necrosis factor
  • TNF is a potent inducer of IL-6 in cultured fibroblasts [Kohase et al., Cell 45:659 (1986)], in various tumor cell lines [Defilippo et al., Proc. Natl. Acad. Sci. (USA) 84:4557 (1987)], and also in man [Jablons et al, J. Immunol. 742:1542 (1989)].
  • This invention provides a method for treating septic shock in a mammal comprising administering to a mammal afflicted with septic shock an effective amount of a combination of an anti-TNF antibody and IL-6.
  • This invention also provides a method for preventing septic shock in a mammal which comprises administering to a mammal susceptible to or at high risk for developing septic shock, an effective amount of a combination of an anti-TNF antibody and IL-6.
  • a pharmaceutical composition comprising a combination of an anti-TNF antibody and IL-6, and a physiologically acceptable carrier, is also provided by this invention.
  • Fig. 1 is a graphical representation of the effects of various treatments administered to groups of 20 mice 18 hours prior to challenge with LPS-gal. Mortality in the groups of mice 24 hours after LPS-gal challenge is shown as a function of pre-treatment with control Dulbecco's phosphate buffered saline (DPBS) and monoclonal antibodies against IL-6 (20F-3) and IL-5 (TRFK-5).
  • DPBS Dulbecco's phosphate buffered saline
  • TRFK-5 monoclonal antibodies against IL-6
  • Fig. 2 is a graphical representation of the effects of various treatments administered to groups of 20 mice 18 hours prior to challenge with LPS-gal. Mortality in the groups of mice 24 hours after LPS-gal challenge is shown, from left to right, as a function of pre-treatment with control Dulbecco's phosphate buffered saline (DPBS), 500 ⁇ g of hamster gamma globulin (HGG), and 50 ⁇ g and 100 ⁇ g of an anti-TNF antibody (TN3) (hamster origin).
  • DPBS Dulbecco's phosphate buffered saline
  • HOG hamster gamma globulin
  • TN3 anti-TNF antibody
  • Fig. 3 is a graphical representation of the effects of varying doses of anti-TNF antibody administered to groups of 20 mice 18 hours prior to challenge with LPS-gal. Mortality in the groups of mice 24 hours after challenge is shown as a function of pre-treatment antibody dose.
  • Fig. 4 is a graphical representation of the effects of various treatments administered to groups of 20 mice prior to challenge with LPS-gal. Mortality in the groups of mice 24 hours after LPS-gal challenge is shown as a function of pre- treatment with 25 ⁇ g/mouse anti-TNF antibody (TN3) with or without 1 mg/mouse anti-IL-6 antibody (20F-3, or with Dulbecco's phosphate buffered saline (DPBS) or 1 mg/mouse hamster gamma globulin (HGG). The results from two experiments are shown using TN3 with or without 20F-3; the DPBS and HGG values shown are the averages from the two experiments. For the combination treatments, p ⁇ 0.05 as determined by the Student's t-test.
  • TN3 25 ⁇ g/mouse anti-TNF antibody
  • DPBS Dulbecco's phosphate buffered saline
  • HGG 1 mg/mouse hamster gamma globulin
  • Fig. 5 is a graphical representation of the effects of varying doses of recombinant IL-6 or 0.57 ⁇ g/mouse control hamster gamma globulin (HGG) administered to groups of 20 mice 1 hour prior to challenge with LPS-gal. The mice had also been treated with 25 ⁇ g/mouse anti-TNF antibody prior to LPS-gal challenge. The mortality in the groups of mice 24 hours after challenge is shown as a function of IL-6 dose.
  • Fig. 6 is a graphical representation of the effects of varying doses of recombinant IL-6 administered to groups of 20 mice 1 hour prior to challenge with LPS-gal. Mortality in the groups of mice 24 hours after challenge is shown as a function of IL-6 dose. The two bars for each IL-6 dose represent the results of two separate experiments. For both IL-6 doses, p > 0.07 as determined by the Student's t-test.
  • septic shock as used herein is defined as a state of morbidity manifesting one or more of the following symptoms: fever or hypothermia [temperature above 38.7°C (101° F) or below 35.6° C (96° F)]; tachycardia (heart rate above 90 beats per minute in the absence of a beta-blockade), tachypnea (respiratory rate above 20 breaths per minute or the requirement of mechanical ventilation); and either hypotension (systolic blood pressure below 90 mm Hg or a sustained drop in systolic pressure above 40 mm Hg in the presence of adequate fluid challenge and the absence of anti-hypertensive agents) or two of the following six signs of systemic toxicity or peripheral hypoperfusion: unexplained metabolic acidosis (blood pH below 7.3, base deficit of greater than 5 mmol per liter, or an elevated plasma lactate level); arterial hypoxemia (partial pressure of oxygen below 75 mm Hg or ratio of the partial pressure of oxygen to the
  • the symptoms listed above are illustrative of specific selection criteria to be used in determining candidates for the proposed method of treatment.
  • States of morbidity which can cause the foregoing symptoms include but are not limited to: acute gram-negative bacteria infections, endotoxemia, purpura fulminans, severe psoriasis, acute rheumatoid arthritis, burns, organ transplant rejection, and physical traumas, such as abdominal wounds.
  • Candidates for abdominal surgery are at high risk for developing septic shock [Debets et al, Crit. Care Med. 7(6):489 (1989)] and could benefit from prophylactic administration of the combination of an anti-TNF antibody and IL-6.
  • the effectiveness of treatment can be assessed by monitoring the above mentioned manifestations of septic shock.
  • Anti-TNF antibodies are available commercially, e.g., Boehringer Mannheim Biochemicals, Indianapolis, IN. IL-6 is commercially available from Genzyme Corporation, Cambridge, MA. Both can also be prepared by known methods using natural sources or recombinant DNA methodologies [Sheehan et al, J. Immunol. 742:884 (1989); Starnes et al, J. Immunol. 745:4185 (1990)].
  • compositions of the invention can be injected directly into the bloodstream intravenously or via an I.V. drip solution such as Ringer's lactate.
  • parenteral preparations that can be used include sterile solutions or suspensions. These preparations can be prepared with conventional pharmaceutically acceptable excipients and additives such as stabilizers and carriers.
  • the solutions to be administered may be reconstituted lyophilized powders which may additionally contain, e.g., preservatives, buffers and dispersants.
  • the compositions are administered by intravenous injection.
  • Kits are also provided by this invention comprising anti-TNF antibodies and IL-6 in physiologically acceptable carriers, in separate containers.
  • monoclonal antibodies can be modified by standard recombinant DNA techniques. Such techniques include but are not limited to the production of antibody variants that combine the rodent variable or hypervariable regions with the human constant or constant and variable framework regions [Rudikoff et al, Proc. Natl. Acad. Sci. USA 79:979 (1982), Morrison and Oi, Adv. Immunol. 44:65 (1989), Queen et al, Proc. Natl. Acad. Sci. USA 86: 10029 (1989)].
  • Humanized antibodies can be generated in which the antigen binding complementarity determining regions (CDRs) from the parent rodent monoclonal antibody are grafted into a human antibody framework.
  • An alternative approach to the production of monoclonal antibodies entails the cloning of the V-region genes from B -cells using the polymerase chain reaction technique. Antibody derivatives are then expressed in a microbial system (e.g. E. coli) and screened for antigen binding ability [Winter and Milstein, Nature 549:293 (1991); Mullinax et al, Proc. Natl. Acad. Sci. USA 87:8095 (1990)]. Heavy and light chain libraries can be prepared in phage lambda and used to generate a large array of random heavy plus light chain pairs expressed in bacteria [Mullinax et al, supra, and Wald ann, Science 252 :1657 (1991)].
  • a microbial system e.g. E. coli
  • Heavy and light chain libraries can be prepared in phage lambda and used to generate a large array of random heavy plus light chain pairs expressed in bacteria [Mullinax et al, supra, and Wald ann, Science 252
  • IL-6 can be made if desired using standard recombinant DNA methods.
  • oligonucleotide probe mixtures based on known IL-6 nucleotide sequences can be used to identify DNA encoding IL-6 in genomic or cDNA libraries prepared by standard methods.
  • DNA thus identified can be excised from the library by restriction endonuclease cleavage or prepared using appropriate primers and the polymerase chain reaction (PCR) method [Saiki et al, Science 259:487 (1988)], sequenced and expressed in a eukaryotic expression system or (following intron deletion by standard methods if necessary) in a prokaryotic or eukaryotic expression system.
  • PCR polymerase chain reaction
  • cDNA and genomic DNA libraries can be screened by the application of standard expression cloning methods, instead of by the use of oligonucleotide probes or PCR.
  • IL-6 thus produced is detected through the use of known immunochemical or bioassay methods.
  • the anti-TNF and the IL-6 used will preferably be those of the mammalian species being treated (e.g., anti-human TNF and human recombinant IL-6 are preferred for treating human beings). It is also preferred that glycosylated IL-6 be used (e.g., recombinant IL-6 produced in a eukaryotic expression system).
  • mammals that are in need of treatment for septic shock as defined above are administered an effective amount of anti- TNF antibodies in combination with IL-6 to accomplish the above-described results.
  • a dose of from about 0.5 ⁇ g to about 250.0 ⁇ g anti-TNF antibodies per kilogram of body weight and about 1.0 ⁇ g to about 3.0 mg IL-6 per kilogram of body weight is preferably administered. More preferably, mammals are administered a dose from about 1.0 ⁇ g to about 3.0 ⁇ g anti-TNF antibody per kilogram of body weight and from about 5.0 ⁇ g to about 30.0 ⁇ g E -6 per kilogram of body weight.
  • administration of the anti-TNF antibody can be concomitant with or prior to administration of the EL-6.
  • the precise amount of the combination of the anti-TNF antibody and the IL-6 to be administered would be determined by the attending clinicians, taking into account the etiology and severity of the disease, the patient's condition, sex, age, and other factors.
  • overnight treatment of mice with the antibodies and cytokines investigated was done in order to facilitate adequate circulating concentrations of these materials in the bloodstream at the time of LPS-gal administration, because intraperitoneal injection of these materials requires a longer diffusion period to enter the bloodstream than other routes of administration (such as intravenous injection).
  • Intraperitoneal injection was selected in this model due to the difficulty of intravenous injection in the mouse.
  • the preferred route of administration would normally be intravenous injection, where bioavailability of the circulating therapeutic agents would be as rapid as 10 minutes.
  • the present invention can be illustrated by the following, non-limiting Example.
  • Anti-mouse TNF (purified TN3-19.12 Ab) was obtained from Dr. Robert D. Schreiber, Washington University, St. Louis, MO. Purified hamster gamma globulin (HGG), a protein control, was purchased from Cappel, Durham, NC. The purified rat anti-mouse IL-5 was obtained from DNAX Institute of Cellular and Molecular Biology, Palo Alto, CA.
  • LPS endotoxin
  • septic shock a component of the outer membrane of gram-negative bacteria
  • LPS a component of the outer membrane of gram-negative bacteria
  • D-galactosamine is a hepatotoxin shown to potentiate the lethal effects of endotoxin (LPS) up to 100,000 fold [Galanos et al, Proc. Natl. Acad. Sci. USA 76:5939 (1979)].
  • LPS endotoxin
  • IL-6 and TNF concentrations were measured in sera obtained 90 minutes after LPS-gal administration.
  • Cytokine -specific enzyme linked immunosorbent assays ELISA's were performed essentially as described by Sheehan et al, and Starnes et al, supra.
  • D-galactosamine was not co-administered with the LPS, animals survived doses of 1.5 mg of LPS for greater than 72 hours.
  • mice were injected i.p. with 1 and 2 mg/mouse anti-IL-6 antibody (20F-3) 1 to 2 hours prior to LPS-gal treatment. [Starnes et al, supra]. Equal amounts of the isotype control of anti-IL-5 antibody (TRFK-5) were used as control proteins. Table I shows that there was no effect on mortality with the anti-IL-6 antibody treatment.
  • Control Ab was anti-IL-5 antibody
  • mice given 50 and 100 ⁇ g i.p. of anti-TNF antibody were protected from death.
  • Fig. 3 shows the average dose relationship of mortality vs. treatment with anti-TNF antibody. Twenty-five ⁇ g/mouse given i.p. the night before LPS-gal administration conferred about 70% protection from death in this model. Doses lower than 10 ⁇ g/mouse conferred very little protection.
  • anti-IL-6 antibody potentiated mortality when TNF was partially neutralized, as shown in Fig. 4.
  • Mice were treated simultaneously with 1 and 2 mg of anti- IL-6 antibody and 25 ⁇ g/mouse anti-TNF antibody 18 hours prior to LPS-gal administration.
  • anti-IL-6 antibody was found to enhance mortality significantly.
  • the same dose plus anti-IL-6 antibody resulted in 65% mortality.
  • the anti-TNF antibody plus IL-6 combination resulted in 45% mortality.
  • mice injected with 100 ng of LPS-gal were bled 90 minutes later.
  • Sera were collected and analyzed for TNF and IL-6 concentration at this time point because this is the time determined for peak concentrations of TNF.
  • Table II illustrates the results allowing for maximum volume of 10 ml/mouse (circulating blood volume plus partitioning into tissue and iterstitial spaces). It was calculated that 100 ng of LPS-gal treatment resulted in 440 ng of IL-6 per mouse. Therefore, 440 ng was the selected dose, plus higher and lower doses in half-log increments to measure the effect of recombinant IL-6 when TNF was partially limited by anti-TNF treatment.
  • Fig. 5 shows that treatment with recombinant mouse IL-6 protected against mortality when TNF was limited by prior administration of anti-TNF antibody.
  • Recombinant IL-6 was given i.p. 1 hour prior to LPS-gal administration. Mice had been treated the night before with 25 ⁇ g/each of anti-TNF antibody. At doses of 132 to 570 ng/mouse, recombinant IL-6 conferred significant protection against mortality. Mortality was lowered from an average in these experiments from 20-0% ( ⁇ 0.05) at 132, 440, and 570 ng/mouse. At lower doses (44 ng and less) no effect was observed. These results demonstrate that the combination of anti-TNF antibody and recombinant IL-6 as a treatment for septic shock is effective in significantly reducing mortality.
  • IL-6 administration 1 hour prior to LPS-gal challenge was substantially ineffective in reducing mortality when the mice did not receive prior treatment with anti-TNF antibody.
  • Fig. 6 where the effects observed with the administration of 0.44 or 0.57 ⁇ g/mouse IL-6 were similar to the results produced by Dulbecco's phosphate buffered saline alone (no IL-6).
  • Fig. 3 The effect of the anti-TNF antibody plus IL-6 is best illustrated by comparing Fig. 3 with Fig. 5.
  • 25 ⁇ g/ml of the anti-TNF antibody conferred only 70% protection from death
  • Fig. 5 that same dose of 25 ⁇ g/ml plus IL-6 (at 132, 440, and 570 ng/ml) conferred 100% protection from death.

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Abstract

L'invention décrit des procédés et des compositions servant au traitement ou à la prévention du choc septique chez un mammifère. Lesdits procédés comprennent l'administration au mammifère atteint d'un choc septique, ou présentant une probabilité élevée d'être atteint par un choc septique, d'une quantité efficace d'une combinaison constitué par un anticorps anti-TNF et de IL-6.
PCT/US1992/010596 1991-12-17 1992-12-15 Utilisation de la combinaison du facteur de necrose anti-tumeur et de l'interleukine-6 dans le traitement du choc septique WO1993011793A1 (fr)

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WO1995006077A2 (fr) * 1993-08-27 1995-03-02 Sandoz Ltd. Matrices polymeres et leurs utilisations dans des compositins pharmaceutiques
EP0668077A1 (fr) * 1994-02-04 1995-08-23 F. Hoffmann-La Roche Ag Compositions contenant G-CSF et une protéine se liant au TNF
WO1996004012A1 (fr) * 1994-08-05 1996-02-15 Schering Corporation Utilisation de la chlorpromazine en combinaison avec l'interleukine-6 pour le traitement ou la prevention du choc septique
US5601814A (en) * 1994-08-05 1997-02-11 Schering Corporation Use of IL-6 to treat toxic shock
US5733742A (en) * 1993-06-03 1998-03-31 Therapeutic Antibodies Inc. Production of antibody fragments from whole blood
WO2002036148A2 (fr) * 2000-11-02 2002-05-10 Apoxis Sa Utilisation de ligands de recepteurs de mort ou rip dans le declenchement de la mort cellulaire independante de la caspase et composes permettant d'inhiber la mort cellulaire independante de la caspase
WO2002100330A2 (fr) 2001-06-08 2002-12-19 Abbott Biotechnology Ltd Methodes d'administration d'anticorps anti-tnf$g(a)
WO2004004633A2 (fr) * 2002-04-26 2004-01-15 Abbott Biotechnology Ltd. Utilisation d'anticorps anti-tnf$g(a) et d'un autre produit pharmaceutique
WO2004016286A2 (fr) 2002-08-16 2004-02-26 Abbott Biotechnology Ltd. Formulation d'anti-corps humains pour le traitement de troubles lies au facteur de necrose tumorale alpha
WO2005110452A2 (fr) 2004-04-09 2005-11-24 Abbott Biotechnology Ltd. Regime posologique a variables multiples destine a traiter des troubles associes a tnf?
US20090263388A1 (en) * 1996-02-16 2009-10-22 The Kennedy Institute Of Rheumatology Methods of preventing or treating cardiovascular, cerebrovascular and thrombotic disorders with tumor necrosis factor antagonists
EP2295071A1 (fr) 2002-10-24 2011-03-16 Abbott Biotechnology Ltd Thérapies faiblement dosées pour traiter des troubles pour lesquels l'activité des facteurs de nécrose tumorale alpha est préjudiciable
EP2305713A1 (fr) 1996-02-09 2011-04-06 Abbott Biotechnology Ltd Anticorps humains se fixant au facteur nécrosant des tumeurs de type alpha
EP2738178A1 (fr) 2006-04-05 2014-06-04 AbbVie Biotechnology Ltd Purification d'anticorps
US8906373B2 (en) 2002-07-19 2014-12-09 Abbvie Biotechnology Ltd. Use of TNF-alpha inhibitor for treatment of psoriasis
US8999337B2 (en) 2007-06-11 2015-04-07 Abbvie Biotechnology Ltd. Methods for treating juvenile idiopathic arthritis by inhibition of TNFα
WO2015073884A2 (fr) 2013-11-15 2015-05-21 Abbvie, Inc. Compositions de protéines de liaison génétiquement glycomodifiées
US9365645B1 (en) 2011-04-27 2016-06-14 Abbvie, Inc. Methods for controlling the galactosylation profile of recombinantly-expressed proteins
US9399061B2 (en) 2006-04-10 2016-07-26 Abbvie Biotechnology Ltd Methods for determining efficacy of TNF-α inhibitors for treatment of rheumatoid arthritis
WO2016160976A2 (fr) 2015-03-30 2016-10-06 Abbvie Inc. Protéines de liaison au tnf monovalentes
EP3078676A1 (fr) 2015-04-10 2016-10-12 Ares Trading S.A. Régime de dosage à induction pour le traitement des maladies liées au tnf alpha
US9499616B2 (en) 2013-10-18 2016-11-22 Abbvie Inc. Modulated lysine variant species compositions and methods for producing and using the same
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US9522953B2 (en) 2013-10-18 2016-12-20 Abbvie, Inc. Low acidic species compositions and methods for producing and using the same
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US9683033B2 (en) 2012-04-20 2017-06-20 Abbvie, Inc. Cell culture methods to reduce acidic species
US9688752B2 (en) 2013-10-18 2017-06-27 Abbvie Inc. Low acidic species compositions and methods for producing and using the same using displacement chromatography
US9708399B2 (en) 2013-03-14 2017-07-18 Abbvie, Inc. Protein purification using displacement chromatography
US9708400B2 (en) 2012-04-20 2017-07-18 Abbvie, Inc. Methods to modulate lysine variant distribution
WO2018124948A1 (fr) 2016-12-30 2018-07-05 Закрытое Акционерное Общество "Биокад" Composition pharmaceutique aqueuse d'un anticorps monoclonal recombinant pour le facteur de nécrose tumorale (tnf) α

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0374510A1 (fr) * 1988-12-19 1990-06-27 American Cyanamid Company Produits pour le traitement de choc endotoxique chez les mammifères

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0374510A1 (fr) * 1988-12-19 1990-06-27 American Cyanamid Company Produits pour le traitement de choc endotoxique chez les mammifères

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
THE JOURNAL OF IMMUNOLOGY vol. 143, no. 11, 1 December 1989, BALTIMORE MD, US pages 3517 - 3523 D. ADERKA ET AL. 'IL-6 inhibits lipopolysaccharide-induced tumor necrosis factor production in cultured human monocytes, U937 cells, and in mice.' cited in the application *

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US6193969B1 (en) 1993-06-03 2001-02-27 Protherics Inc. Antibody fragments in therapy
WO1995006077A3 (fr) * 1993-08-27 1995-05-04 Sandoz Ltd Matrices polymeres et leurs utilisations dans des compositins pharmaceutiques
US6083521A (en) * 1993-08-27 2000-07-04 Novartis Ag Polymeric matrices and their uses in pharmaceutical compositions
US6262127B1 (en) 1993-08-27 2001-07-17 Novartis Ag Polymeric matrices and their uses in pharmaceutical compositions
WO1995006077A2 (fr) * 1993-08-27 1995-03-02 Sandoz Ltd. Matrices polymeres et leurs utilisations dans des compositins pharmaceutiques
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EP0668077A1 (fr) * 1994-02-04 1995-08-23 F. Hoffmann-La Roche Ag Compositions contenant G-CSF et une protéine se liant au TNF
US5750503A (en) * 1994-02-04 1998-05-12 Hoffmann-La Roche Inc. Compositions of G-CSF and TNF-BP for prophylaxis and treatment of septic shock
US5776895A (en) * 1994-02-04 1998-07-07 Hoffman-La Roche Inc. Compositions of G-CSF and TNF-BP for prophylaxis and treatment of septic shock
WO1996004012A1 (fr) * 1994-08-05 1996-02-15 Schering Corporation Utilisation de la chlorpromazine en combinaison avec l'interleukine-6 pour le traitement ou la prevention du choc septique
US5601814A (en) * 1994-08-05 1997-02-11 Schering Corporation Use of IL-6 to treat toxic shock
EP2357200A1 (fr) 1996-02-09 2011-08-17 Abbott Biotechnology Ltd Anticorps humains se fixant au facteur necrosant des tumeurs de type alpha
EP2305712A1 (fr) 1996-02-09 2011-04-06 Abbott Biotechnology Ltd Anticorps humains se fixant au facteur necrosant des tumeurs de type alpha
EP2397494A1 (fr) 1996-02-09 2011-12-21 Abbott Biotechnology Ltd Anticorps humains qui se lient au TNFalpha
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US20090263388A1 (en) * 1996-02-16 2009-10-22 The Kennedy Institute Of Rheumatology Methods of preventing or treating cardiovascular, cerebrovascular and thrombotic disorders with tumor necrosis factor antagonists
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US9073987B2 (en) 2001-06-08 2015-07-07 Abbvie Biotechnology Ltd. Methods of administering anti-TNFα antibodies
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US9017680B2 (en) 2001-06-08 2015-04-28 Abbvie Biotechnology Ltd. Methods of administering anti-TNFα antibodies
US8992926B2 (en) 2001-06-08 2015-03-31 Abbvie Biotechnology Ltd. Methods of administering anti-TNFα antibodies
EP2940044A1 (fr) 2001-06-08 2015-11-04 AbbVie Biotechnology Ltd Procédés d'administration d'anticorps anti-tnfalpha
US8889135B2 (en) 2001-06-08 2014-11-18 Abbvie Biotechnology Ltd. Methods of administering anti-TNFα antibodies
EP2196218A2 (fr) 2002-04-26 2010-06-16 Abbott Biotechnology Ltd Utilisation d'anticorps anti-TNFalpha et d'un autre médicament
EP2347766A1 (fr) 2002-04-26 2011-07-27 Abbott Biotechnology Ltd Utilisation d'anticorps anti-TNF dollar g(a) et d'un autre produit pharmaceutique
WO2004004633A3 (fr) * 2002-04-26 2004-06-10 Abbott Biotech Ltd Utilisation d'anticorps anti-tnf$g(a) et d'un autre produit pharmaceutique
WO2004004633A2 (fr) * 2002-04-26 2004-01-15 Abbott Biotechnology Ltd. Utilisation d'anticorps anti-tnf$g(a) et d'un autre produit pharmaceutique
US8906373B2 (en) 2002-07-19 2014-12-09 Abbvie Biotechnology Ltd. Use of TNF-alpha inhibitor for treatment of psoriasis
US9085620B1 (en) 2002-07-19 2015-07-21 Abbvie Biotechnology Ltd. Use of TNFα inhibitor for treatment of psoriatic arthritis
US9090689B1 (en) 2002-07-19 2015-07-28 Abbvie Biotechnology Ltd. Use of TNFα inhibitor for treatment of psoriasis
EP2363145A1 (fr) 2002-08-16 2011-09-07 Abbott Biotechnology Ltd Formulation d'anticorps humains pour le traitement de troubles associés au tnf-alpha
EP2359856A1 (fr) 2002-08-16 2011-08-24 Abbott Biotechnology Ltd Formulation d'anticorps humains pour le traitement de troubles associés au TNF-alpha
US8911741B2 (en) 2002-08-16 2014-12-16 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-alpha associated disorders
US8916158B2 (en) 2002-08-16 2014-12-23 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-α associated disorders
US8916157B2 (en) 2002-08-16 2014-12-23 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-α associated disorders
US8932591B2 (en) 2002-08-16 2015-01-13 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-α associated disorders
US8940305B2 (en) 2002-08-16 2015-01-27 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-α associated disorders
US9302011B2 (en) 2002-08-16 2016-04-05 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-α associated disorders
US9295725B2 (en) 2002-08-16 2016-03-29 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
WO2004016286A2 (fr) 2002-08-16 2004-02-26 Abbott Biotechnology Ltd. Formulation d'anti-corps humains pour le traitement de troubles lies au facteur de necrose tumorale alpha
EP2363144A1 (fr) 2002-08-16 2011-09-07 Abbott Biotechnology Ltd Formulation d'anticorps humains pour le traitement de troubles associés au TNF-alpha
EP2361637A1 (fr) 2002-08-16 2011-08-31 Abbott Biotechnology Ltd Formulation d'anticorps humains pour le traitement de troubles associés au TNF-alpha
US9289497B2 (en) 2002-08-16 2016-03-22 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US9327032B2 (en) 2002-08-16 2016-05-03 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US9272042B2 (en) 2002-08-16 2016-03-01 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US9272041B2 (en) 2002-08-16 2016-03-01 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US9220781B2 (en) 2002-08-16 2015-12-29 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US9732152B2 (en) 2002-08-16 2017-08-15 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US9738714B2 (en) 2002-08-16 2017-08-22 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
US9750808B2 (en) 2002-08-16 2017-09-05 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-alpha associated disorders
US9114166B2 (en) 2002-08-16 2015-08-25 Abbvie Biotechnology Ltd. Formulation of human antibodies for treating TNF-α associated disorders
US9950066B2 (en) 2002-08-16 2018-04-24 Abbvie Biotechnology Ltd Formulation of human antibodies for treating TNF-alpha associated disorders
EP2295071A1 (fr) 2002-10-24 2011-03-16 Abbott Biotechnology Ltd Thérapies faiblement dosées pour traiter des troubles pour lesquels l'activité des facteurs de nécrose tumorale alpha est préjudiciable
EP2332565A1 (fr) 2002-10-24 2011-06-15 Abbott Biotechnology Ltd. Thérapies faiblement dosées pour traiter des troubles pour lesquels l'activité des facteurs de nécrose tumorale alpha est préjudiciable
US8846046B2 (en) 2002-10-24 2014-09-30 Abbvie Biotechnology Ltd. Low dose methods for treating disorders in which TNFα activity is detrimental
US8986693B1 (en) 2004-04-09 2015-03-24 Abbvie Biotechnology Ltd. Use of TNFα inhibitor for treatment of psoriasis
US8961973B2 (en) 2004-04-09 2015-02-24 Abbvie Biotechnology Ltd. Multiple-variable dose regimen for treating TNFα-related disorders
US9499615B2 (en) 2004-04-09 2016-11-22 Abbvie Biotechnology Ltd Multiple-variable dose regimen for treating idiopathic inflammatory bowel disease
US9061005B2 (en) 2004-04-09 2015-06-23 Abbvie Biotechnology Ltd Multiple-variable dose regimen for treating idiopathic inflammatory bowel disease
WO2005110452A2 (fr) 2004-04-09 2005-11-24 Abbott Biotechnology Ltd. Regime posologique a variables multiples destine a traiter des troubles associes a tnf?
US9187559B2 (en) 2004-04-09 2015-11-17 Abbvie Biotechnology Ltd Multiple-variable dose regimen for treating idiopathic inflammatory bowel disease
EP2338516A2 (fr) 2004-04-09 2011-06-29 Abbott Biotechnology Ltd Régimes posologiques multiples et variables pour traiter les troubles liés au TNF-alpha
EP2335731A2 (fr) 2004-04-09 2011-06-22 Abbott Biotechnology Ltd Régime posologique à variables multiples destiné à traiter des troubles associés à TNF-alpha
US8961974B2 (en) 2004-04-09 2015-02-24 Abbvie Biotechnology Ltd. Multiple-variable dose regimen for treating TNFα-related disorders
US8889136B2 (en) 2004-04-09 2014-11-18 Abbvie Biotechnology Ltd. Multiple-variable dose regimen for treating TNFα-related disorders
EP2335732A2 (fr) 2004-04-09 2011-06-22 Abbott Biotechnology Ltd RÉGIME POSOLOGIQUE À VARIABLES MULTIPLES DESTINÉ A TRAITER DES MALADIES ASSOCIÉES À TNFalpha
US9512216B2 (en) 2004-04-09 2016-12-06 Abbvie Biotechnology Ltd. Use of TNFα inhibitor
US9067992B2 (en) 2005-05-16 2015-06-30 Abbvie Biotechnology Ltd. Use of TNFα inhibitor for treatment of psoriatic arthritis
EP3088410A2 (fr) 2006-04-05 2016-11-02 AbbVie Biotechnology Ltd Purification d'anticorps
EP2738179A1 (fr) 2006-04-05 2014-06-04 AbbVie Biotechnology Ltd Purification d'anticorps
EP2738178A1 (fr) 2006-04-05 2014-06-04 AbbVie Biotechnology Ltd Purification d'anticorps
US9399061B2 (en) 2006-04-10 2016-07-26 Abbvie Biotechnology Ltd Methods for determining efficacy of TNF-α inhibitors for treatment of rheumatoid arthritis
US9624295B2 (en) 2006-04-10 2017-04-18 Abbvie Biotechnology Ltd. Uses and compositions for treatment of psoriatic arthritis
US9605064B2 (en) 2006-04-10 2017-03-28 Abbvie Biotechnology Ltd Methods and compositions for treatment of skin disorders
US9669093B2 (en) 2007-06-11 2017-06-06 Abbvie Biotechnology Ltd Methods for treating juvenile idiopathic arthritis
US8999337B2 (en) 2007-06-11 2015-04-07 Abbvie Biotechnology Ltd. Methods for treating juvenile idiopathic arthritis by inhibition of TNFα
US9284370B1 (en) 2007-06-11 2016-03-15 Abbvie Biotechnology Ltd. Methods for treating juvenile idiopathic arthritis
US9505834B2 (en) 2011-04-27 2016-11-29 Abbvie Inc. Methods for controlling the galactosylation profile of recombinantly-expressed proteins
US9365645B1 (en) 2011-04-27 2016-06-14 Abbvie, Inc. Methods for controlling the galactosylation profile of recombinantly-expressed proteins
US9708400B2 (en) 2012-04-20 2017-07-18 Abbvie, Inc. Methods to modulate lysine variant distribution
US9505833B2 (en) 2012-04-20 2016-11-29 Abbvie Inc. Human antibodies that bind human TNF-alpha and methods of preparing the same
US9957318B2 (en) 2012-04-20 2018-05-01 Abbvie Inc. Protein purification methods to reduce acidic species
US9683033B2 (en) 2012-04-20 2017-06-20 Abbvie, Inc. Cell culture methods to reduce acidic species
US9512214B2 (en) 2012-09-02 2016-12-06 Abbvie, Inc. Methods to control protein heterogeneity
US9499614B2 (en) 2013-03-14 2016-11-22 Abbvie Inc. Methods for modulating protein glycosylation profiles of recombinant protein therapeutics using monosaccharides and oligosaccharides
US9708399B2 (en) 2013-03-14 2017-07-18 Abbvie, Inc. Protein purification using displacement chromatography
US9598667B2 (en) 2013-10-04 2017-03-21 Abbvie Inc. Use of metal ions for modulation of protein glycosylation profiles of recombinant proteins
US9499616B2 (en) 2013-10-18 2016-11-22 Abbvie Inc. Modulated lysine variant species compositions and methods for producing and using the same
US9688752B2 (en) 2013-10-18 2017-06-27 Abbvie Inc. Low acidic species compositions and methods for producing and using the same using displacement chromatography
US9522953B2 (en) 2013-10-18 2016-12-20 Abbvie, Inc. Low acidic species compositions and methods for producing and using the same
WO2015073884A2 (fr) 2013-11-15 2015-05-21 Abbvie, Inc. Compositions de protéines de liaison génétiquement glycomodifiées
US9550826B2 (en) 2013-11-15 2017-01-24 Abbvie Inc. Glycoengineered binding protein compositions
WO2016160976A2 (fr) 2015-03-30 2016-10-06 Abbvie Inc. Protéines de liaison au tnf monovalentes
WO2016162537A1 (fr) 2015-04-10 2016-10-13 Ares Trading S.A Schéma posologique d'induction
EP3078675A1 (fr) 2015-04-10 2016-10-12 Ares Trading S.A. Régime de dosage à induction pour le traitement des maladies liées au tnf alpha
EP3078676A1 (fr) 2015-04-10 2016-10-12 Ares Trading S.A. Régime de dosage à induction pour le traitement des maladies liées au tnf alpha
WO2018124948A1 (fr) 2016-12-30 2018-07-05 Закрытое Акционерное Общество "Биокад" Composition pharmaceutique aqueuse d'un anticorps monoclonal recombinant pour le facteur de nécrose tumorale (tnf) α

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