Classifications

• • 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
  • A61K38/19—Cytokines; Lymphokines; Interferons
  • A61K38/20—Interleukins [IL]
  • A61K38/204—IL-6

Definitions

• He atopoiesis the proliferation and differentiation of blood cells from pluripotent stem cells, has been found to be "regulated by a variety of cell factors, i.e. cytokines, examples of which are the interleukins (JL's) and the colony-stimulating factors (CSF's) .
• cytokines examples of which are the interleukins (JL's) and the colony-stimulating factors (CSF's) .
• Human interleukin-6 (IL-6) is produced by the lymphoid and other cells and plays a role in stimulating proliferation of multiple lineages of hematopoietic cells.
• activities ascribed to IL-6 include antiviral activity, stimulation of B-cells and Ig secretion, induction of IL-2 and IL-2 receptor expression, enhancement of IL-3 induced colony formation, proliferation and differentiation of T-cells, maturation of megakaryocytes, and other functions.
• the pleiotropic or multifunctional nature of human IL-6 is reflected in the plurality of names used [e.g. interferon- ⁇ 2 (IFN ⁇ *-,) , 26 kDA protein (26 K) , B-cell stimulatory factor 2 (BSF-2) , hybridoma/plasmacytoma growth factor (HPGF) , hepatocyte stimulating factor (HSF) and cytotoxic T-cell differentiation factor (CDF) ] to refer to what has been confirmed by molecular cloning to be a single protein of 212 amino acids and a molecular mass ranging from 21 to 28 kd, depending on the cellular source and preparation [Van Snick, Ann .Rev.Immunol. 8. (1990) 253-257] . Recombinant human IL-6 protein has been molecularly cloned and purified to homogeneity.
• IFN ⁇ *-, 26 K B-cell stimulatory factor 2
• HPGF hybridoma/plasmacytoma growth
• IL-6 and IL-6 protein refer to the natural or recombinantly prepared protein, which may be glycosylated or unglycosylated and which substantially has the amino acid sequence of natural human IL-6 as disclosed, for example, in WO 88/206.
• a well-documented inter-species activity of human IL-6 comprises stimulation of thrombocytopoiesis, i.e. the process by which megakaryocyte progenitor cells mature into megakaryocytes, from which the platelets are ultimately released into the peripheral circulation.
• thrombocytopoiesis i.e. the process by which megakaryocyte progenitor cells mature into megakaryocytes, from which the platelets are ultimately released into the peripheral circulation.
• rhIL-6 recombinant human IL-6
• rhIL-6 recombinant human IL-6
• IL-6 induced platelet production has also been documented in a non-human primate model of radiation-induced marrow aplasia, as well as in humans receiving anticancer chemotherapy.
• the platelets contribute a vital homeostatic function by adhering and coagulating on damaged tissue and by secreting factors which initiate coagulation reactions.
• a deficiency of platelets thrombocytopenia
• thrombocytopenia can be a life-threatening condition, for which the only conventional treatments have been repeated platelet transfusions or bone marrow transplantation, both involving, among many others, risks of infection.
• IL-6 may therefore be practiced as an endogenous means of accelerating recovery from thrombocytopenia, and may even spare the need for transfusion or transplantation.
• IL-6 may also be used and is particularly important in treating subjects in whom thrombocytopenia has been induced by irradiation or administration of drugs which interfere with hematopoiesis.
• IL-6 therapy administration of IL-6 therapy to a patient for purposes of obtaining the various benefits and advantages therefrom, including, in particular, stimulation of thrombocytopoiesis, or for other therapeutic purposes, is often accompanied by associated systemic changes which, at higher dosages of IL-6 or over prolonged periods of time, may interfere with attainment of the therapeutic goal.
• IL-6 administration has been linked to certain responses by the liver which otherwise typically characterize the mammalian "acute phase response" to a challenge such as inflammation or tissue injury.
• Symptoms of the acute phase response include alteration in plasma protein levels and steroid concentrations, as evidenced by an increased erythrocyte sedimentation rate (ESR) , as well as leukocytosis, increased vascular permeability, fever, patient malaise, discomfort, fatigue, weight loss and pallor.
• ESR erythrocyte sedimentation rate
• IL-6 has been found to act on the hepatocytes to regulate production therein of certain plasma proteins typically associated with the acute phase response, which are referred to as "acute phase proteins" (APP's) [Gauldie et al. , PNAS USA £4. (1987) 7251; Geiger et al. , Eur.J.Immunol. 18 (1988) 717].
• acute phase proteins include both "up-regulated” proteins, plasma levels of which are increased in response to IL-6 administration, and “down-regulated” proteins, plasma levels of which are depressed by IL-6.
• up-regulated acute phase proteins examples include ⁇ -antitrypsin, haptoglobulin, ceruloplasmin, c ⁇ -acid glycoprotein, C-reactive protein (CRP) , ⁇ -globulin, ⁇ 2 -macroglobulin, serum amyloid A protein and fibrinogen.
• CRP C-reactive protein
• ⁇ -globulin ⁇ 2 -macroglobulin
• serum amyloid A protein and fibrinogen examples of a "down-regulated” protein comprises prealbumin [Pepys, "Acute Phase Proteins", in Encyclopedia of Immunology. I, Roitt, Ed., Academic Press (1992) 16-18] .
• IL-6 The extent of an acute phase response accompanying in vivo administration of IL-6 can be correlated to measurable changes in the serum levels of such circulating acute phase proteins.
• Studies in normal rhesus monkeys demonstrate that IL-6 administration is accompanied by a dose-related increase in serum levels of positively regulated acute phase proteins, e.g. CRP, o 2 -macroglobulin and fibrinogen, and likewise, by a dose-related decrease in negatively regulated prealbumin [Mayer et al. , Exp.Hematol. 19 (1991) 688-696].
• up-regulated acute phase proteins including CRP and fibrinogen increased during therapy fBlood 80 No.10.
• G-CSF Granulocyte colony stimulating factor
• GM-CSF granulocyte- macrophage colony stimulating factor
• G-CSF can promote an increase in the number of circulating neutrophils, which assist in protecting the body against infection
• GM-CSF acts as a growth factor for granulocyte, monocyte and eosinophil progenitors, and its administration in human and non-human primates results in increased numbers of circulating neutrophils as well as eosinophils, monocytes and lymphocytes.
• G-CSF and GM-CSF are particularly useful in accelerating recovery from neutropenia in patients subjected to radiation or chemotherapy, or following bone marrow transplantation.
• G-CSF and G-CSF protein refer to a natural or recombinantly prepared protein having substantial identity to the amino acid sequence of natural human G-CSF as disclosed, for example, in USP 4'999 '291 or, respectively, to an amino acid sequence of human GM-CSF as disclosed, for example in WO 86/639.
• Recombinant human G-CSF and GM-CSF are hereinafter also referred to as "rhG-CSF” and, respectively, “rhGM-CSF” .
• co-administration of preferably at least an equal weight amount of G-CSF or GM-CSF with IL-6 can mitigate IL-6-mediated changes in circulating levels of acute phase proteins, especially, can reduce or suppress IL-6-mediated changes in circulating levels of up-regulated acute phase proteins.
• G-CSF and GM-CSF when each is co-administered with IL-6, e.g. in the hereinafter indicated minimum ratio relative to IL-6, surprisingly, cooperate in an as yet unknown manner to reduce or suppress aspects of the acute phase response without foregoing the primary therapeutic uses of IL-6 such as thrombocytopoiesis, and without lessening the neutrophil stimulation provided by the CSF when also administered in an amount sufficient to effect such stimulation.
• the present invention therefore comprises a method for reducing or suppressing the acute phase response, particularly the increase in serum levels of up-regulated APPs, in a patient receiving IL-6 therapy which comprises co-administering with the IL-6 an acute phase protein level mitigating effective amount of G-CSF or GM-CSF or a functional equivalent thereof.
• Patients to be treated include mammals, including human and non-human primates, especially humans.
• the invention also provides corresponding agents or pharmaceutical compositions comprising a therapeutically effective amount of the combination of IL-6 and an acute phase protein level mitigating effective amount of G-CSF or GM-CSF or a functional equivalent thereof, together with at least one pharmaceutically acceptable carrier or diluent.
• FIGS. l-7a comprise a series of graphs which demonstrate the effect on various aspects of the acute phase response of administering to rhesus monkeys a course of therapy comprising either of: rhIL-6 (Group I); rhGM-CSF (Group II); rhG-CSF (Group III); rhIL-6 and rhGM-CSF (Group IV) ; or rhIL-6 and rhG-CSF (Group V) .
• FIGS. 1 and la depict changes in the average platelet concentration of each group from baseline levels
• FIGS. 2 and 2a depict changes in average neutrophil level of each group from baseline levels
• FIGS. 3 and 3a are bar graphs representing changes in average erythrocyte sedimentation rate (ESR) ;
• FIGS. 4 and 4a are bar graphs showing the baseline average serum ⁇ 2 -macroglobulin concentration for each group prior to cytokine administration;
• FIGS. 5 and 5a show the average serum ⁇ 2 -macroglobulin concentration following administration of cytokine
• FIGS. 6 and 6a are bar graphs showing the average baseline serum fibrinogen concentration for each group prior to cytokine administration
• FIGS. 7 and 7a are bar graphs showing the average fibrinogen concentration for each group following administration of cytokine.
• Human IL-6 may be purified from natural sources or produced by recombinant means in conventional manner. G-CSF and GM-CSF can also be similarly obtained. Preferably the cytokines are obtained by culturing transformants obtained by transforming a host with recombinant DNA comprising at least the human cDNA under the control of a suitable promoter. Preferred methods of recombinantly producing mammalian IL-6, G-CSF and GM-CSF involve expression in bacteria or yeast cells, although recombinant proteins can also be produced using mammalian cells, insect cells, or other cells under the control of appropriate promoters.
• the proteins can be glycosylated to varying degrees or unglycosylated.
• E. coli derived, non-glycosylated or mammalian cell-produced, glycosylated rhIL-6 can be obtained by the methods described e.g. in WO 88/206.
• E. coli-derived, non-glycosylated rhG-CSF is commercially available from Amgen Inc. (Thousand Oaks, CA, USA) under the tradename Neupogen R , and glycosylated forms may be produced by known means.
• E. coli-derived, non-glycosylated rhGM-CSF is commercially available from Sandoz Ltd. (Basle, Switzerland) under the tradename Leucomax R , or can be obtained by the methods described e.g. in WO 86/639, wherein two native GM-CSFs differing by a single amino acid are described.
• the natural human IL-6 and G-CSF and GM-CSF proteins may be modified by changing their amino acid sequence. For example, from 1 to 5 amino acids in their sequences may be changed, or their sequences may be lengthened without changing their fundamental character, and modified proteins which are the full functional equivalents of the native proteins may be provided which can also be used in practicing the present invention.
• a GM-CSF differing by a single amino acid from the common native sequence is disclosed e.g. in USP 5'229'496 and has been produced in glycosylated form in yeast, and has been clinically demonstrated to be a biological equivalent of native GM-CSF, such modified form being known as GM-CSF(Leu-23) .
• the natural or recombinantly prepared proteins and their functional equivalents used in the present invention are preferably purified and substantially cell-free. This may be accomplished by known procedures.
• Reduction or suppression of the acute phase response in a patient receiving IL-6 therapy preferably is effected by co-administering to the patient an acute phase mitigating effective amount of G-CSF or GM-CSF which is preferably equal to or greater than the amount of the IL-6, the amount of each being expressed as unglycosylated protein.
• the extent of an acute phase response in a patient receiving IL-6 therapy appears to be correlated to changes in serum levels of certain acute phase proteins, in particular CRP, ⁇ 2 -macroglobulin and fibrinogen. Therefore, the extent of an acute phase response in a subject being administered IL-6 can be determined based on the difference between the baseline serum level of one or more circulating acute phase proteins, i.e. the level prior to initial administration of IL-6, and the serum level of the protein following commencement of IL-6 administration.
• the unexpected effect of G-CSF or GM-CSF co-administration with the IL-6 can be determined by comparing the serum level of one or more acute phase proteins taken after initial administration of IL-6 alone, with the serum level taken after G-CSF or GM-CSF is co-administered with IL-6.
• Baseline levels of protein may be measured at any time prior to IL-6 administration, preferably within 3-4 weeks, and more preferably within 2 weeks or 1 week, prior to the IL-6 therapy.
• Post- administration protein levels are preferably determined after four days of administration of the combination and within 24 hours of the IL-6 dosing.
• serum samples are taken before the IL-6 is completely metabolized, most preferably within 6 hours of IL-6 administration to the patient.
• Periodic monitoring e.g. every 3 to 7 days, will take place over the longer treatment periods, and upon completion of treatment.
• ESR erythrocyte sedimentation rate
• Reduction or suppression of the acute phase response by co-administering G-CSF or GM-CSF to subjects receiving IL-6 therapy has been found to be achieved without apparent adverse effect on certain primary therapeutic functions of either cytokine, such as the activity of IL-6 in stimulating thrombocytopoiesis, or of the activity of G-CSF and GM-CSF to increase neutrophil production.
• co-administration administration of the total daily dosage of each respective cytokine preferably within a common time period of no greater than 15 hours, e.g. one cytokine at 6 p.m. and the other the following 9 a.m. The period is preferably no greater than 8 hours or 4 hours, even more preferably no greater than 2 hours.
• the G-CSF or GM-CSF is administered within 2 hours or less of IL-6 administration, since the half-life of IL-6 in the body is about 2-4 hours. More preferably, the G-CSF or GM-CSF is administered within 1 hour down to 30 minutes, or even fifteen minutes of IL-6 administration.
• the total daily dosage of the cytokines are administered simultaneously or virtually simultaneously.
• administration of the cytokines may be made in any time order provided that the complete dose of each cytokine has been administered over a 15-hour period or lesser periods as described above.
• a suitable dosage regimen will be determined based on various factors affecting the action of drugs, e.g. body weight, sex and diet of the patient, severity of infection, time of administration, etc.
• the IL-6 will be administered in an amount effective to increase the platelet count of the patient.
• An effective daily dose of IL-6 for such purposes will range from about 0.5,. ⁇ g/kg to about 20 ⁇ g/kg body weight, expressed as non-glycosylated IL-6, more usually from about 0.5 ⁇ g/kg to about 10 ⁇ g/kg, preferably from about 1 ⁇ g/kg to about 8 ⁇ g/kg, and especially from about 1 ⁇ g/kg to about 6 ⁇ g/kg.
• the more preferred effective amount of IL-6 usually ranges from about 1.5 ⁇ g/kg to about 5 ⁇ g/kg per day, and can be e.g. 0.5 ⁇ g/kg/day in the treatment of bone marrow transplant patients or 1.0 ⁇ g/kg/day in post-chemotherapy treatment.
• the amount of G-CSF or GM-CSF to be administered will be an amount effective to reduce or suppress the acute phase response to IL-6 and may be expressed as a weight ratio relative to the IL-6.
• the weight ratio of G-CSF or GM-CSF to IL-6 will preferably be at least about 1:1 with both cytokines being expressed as non-glycosylated protein.
• Increasing the weight ratio of G-CSF or GM-CSF to IL-6 above the 1:1 ratio may be used to further reduce or suppress the acute phase response.
• ratios up to about 8:1 or even greater may be used.
• the ratio of G-CSF or GM-CSF to IL-6 may therefore range from about 1:1 to about 8:1 or may be even higher.
• the weight ratio of G-CSF or GM-CSF to IL-6 will be in the range of from about 1:1 to about 6:1, with very good results indicated at a ratio of 1:1 or somewhat higher, e.g. at least about 2:1, or in the range of from about 1:1 or 2:1 to about 5:1, the proteins being expressed as a non-glycosylated protein.
• the daily dosage of G-CSF or GM-CSF may range from about 1 ⁇ g/kg to about 20 ⁇ g/kg body weight, more usually from about 1 ⁇ g/kg to about 10 ⁇ g/kg.
• the more preferred effective amount of G-CSF is from about 2 ⁇ g/kg to about 8 ⁇ g/kg per day and more preferably from about 3 ⁇ g/kg to about 8 ⁇ g/kg per day, preferably from about 4 ⁇ g/kg/day to about 6 ⁇ g/kg/day, especially about 5 ⁇ g/kg/day for bone marrow transplant patients or post-chemotherapy treatment, expressed as non-glycosylated G-CSF;
• the more preferred amount of GM-CSF is from about 1.5 ⁇ g/kg to about 8 ⁇ g/kg per day and more preferably from about 2 ⁇ g/kg to about 6 ⁇ g/kg per day, expressed as non-glycosylated GM-CSF (a dose of cytokine may also be expressed in terms of body surface rather than ⁇ g/kg; thus a dose of 6 ⁇ g/kg/day corresponds, for a 72 kg subject with an average body surface area of 1.73 m 2 , to about 250 ⁇ g/m 2 /
• the G-CSF may be administered at a dose of from 2 to 8 ⁇ g/kg/day and the weight ratio of G-CSF to IL-6 may be at least 2:1.
• the GM-CSF may be administered at a dose of from 2.0 to 6 ⁇ g/kg/day and the weight ratio of GM-CSF to IL-6 is at least about 2:1.
• An effective treatment with IL-6 to increase platelets will generally take place over several days, typically over a 4- to 21-day period which may be interrupted for a day or two, and which may be repeated after a few days interruption, depending upon the cause of the deficiency in platelets, for example, the periods of chemotherapy treatment.
• the method of the invention will be carried out by administering to a patient a composition comprising the purified protein in conjunction with physiologically acceptable carriers, excipients or diluents such as neutral buffered saline, or saline mixed with serum albumin.
• physiologically acceptable carriers such as neutral buffered saline, or saline mixed with serum albumin.
• compositions can be administered parenterally.
• parenteral administration include subcutaneous, intravenous, intra-arterial, intramuscular and intraperitoneal, with subcutaneous administration being preferred.
• the IL-6 and G-CSF or GM-CSF will generally be formulated in a unit dosage injectable form (solution, suspension, emulsion) , preferably in a pharmaceutically acceptable carrier medium.
• a pharmaceutically acceptable carrier medium examples include saline, Ringer's solution, dextrose solution, mannitol and normal serum albumin.
• Neutral buffered saline or saline mixed with serum albumin are exemplary appropriate vehicles.
• Non-aqueous vehicles such as fixed oils and ethyl oleate may also be used.
• Additional additives include substances to enhance isotonicity and chemical stability, e.g. buffers, preservatives and surfactants, such as Polysorbate 80.
• parenterally acceptable protein solutions of proper pH, isotonicity, stability, etc.
• the product is formulated by known procedures as a lyophilizate using appropriate excipient solutions such as sucrose as a diluent.
• the cytokines may be combined before administration to the patient and administered together, or alternatively, they can be administered separately. Separate, but substantially concurrent administration is generally preferred. A single administration may be possible as an injection provided the proteins are suitably combined.
• the therapy may be administered to mammals, particularly primates, including human and non-human primates, and especially humans.
• An acute phase protein level mitigating effective amount of G-CSF or GM-CSF is an amount such that upon co-administration with IL-6 the serum level of up-regulated APPs is mitigated - (mildened/moderated/reduced) to about 90 %, preferably to about 50-60 % of the level with IL-6 alone.
• Example 1 Sources of recombinant cvtokines
• rhIL-6 rhIL-6 is prepared from recombinant E. coli as a non-glycosylated, N-methionine terminated protein according to the method described in WO 88/206.
• the rhIL-6 that accumulates intracellularly is extracted from E. coli cells expressing IL-6 cDNA from a plasmid vector and purified to homogeneity by a series of known chromatographic steps, including high-performance liquid chromatography (HPLC) and column chromatography.
• HPLC high-performance liquid chromatography
• SDS-PAGE Sodium dodecyl sulfate-polyacrylamide gel electrophoresis demonstrates the presence of a single Coomassie blue staining band with a purity above 98 %.
• the specific activity is 9.2 x 10 7 U/mg protein, assayed using the mouse cell line B13.29 bioassay [Lansdorp et al. , Current Topics in Microbiology and Immunology. Springer-Verlag, 132 (1986) 105-113].
• the IL-6 is formulated into a sodium phosphate buffered saline solution containing Polysorbate 80, sucrose and glycine, pH about 7.5, and lyophilized.
• the lyophilizate is reconstituted for the subcutaneous treatment by thawing in water.
• the solutions have a specific activity of approximately 11.9 x 10 7 U/mg protein.
• Neupogen R is obtained from Amgen Inc. (Thousand Oaks, CA, USA). Each single vial of Neupogen R contains 300 ⁇ g/ml of recombinant E. coli-derived non-glycosylated methionyl human G-CSF (R-metHuG-CSF) having a specific activity of 1.0 ⁇ 0.6 x 10 B U/mg.
• the protein is formulated in 10 mM sodium acetate buffer at pH 4.0 containing 5 % mannitol and 0.004 % Tween R 80. The manufacture, purification and formulation of Neupogen R is also described further in The Physician's Desk Reference (1993) 605. 3 . rhGM-CSF
• Non-glycosylated, rhGM-CSF is e.g. obtained from recombinant E. coli as described in WO 86/639.
• the crude protein extract is purified by anion exchange chromatography followed by gel filtration chromatography.
• the pooled fractions which constitute the purified GM-CSF are filtered and stored at -80°.
• the specific activity, as determined by bioassay and HPLC, is 2.63 - 3.29 x IO 8 U/mg protein.
• Example 2 APP levels upon co-administration in monkevs
• Subjects Fifteen young adult male Rhesus monkeys, Macaca mulatta, approximately 4 years old and weighing between 3.5 and
• the monkeys are housed individually in stainless steel squeeze cages in an air-conditioned room.
• the monkeys are fed Purina Certified Primate Chow and have access to food and water ad libitum.
• the temperature and humidity are maintained at 26° ⁇ 2° and 50 % ⁇ 20 %, respectively.
• Fresh fruit is given daily to supplement the routine food source.
• the fifteen monkeys are randomly assigned to five groups of 3 animals each.
• Baseline Levels of ⁇ -,-macroglobulin and fibrinogen o 2 -macro- globulin and fibrinogen levels (mg/dl) of each test subject are taken to determine base level activity.
• the average base level for each group of 3 monkeys is graphically represented on Figures 4 and 4a and 6 and 6a, respectively.
• each subject receives a daily subcutaneous injection of IL-6 and/or Neupogen R or rhGM-CSF containing each cytokine as follows:
• Group V 20 + 20 rhIL-6 + rhG-CSF Daily clinical observations and weekly body weights are recorded during weeks -3 to 5. Eye examinations are performed in weeks -3 and 5. Blood is withdrawn for clinical pathology and immunology determinations and testing for baseline levels of platelets, neutrophils, and acute phase proteins, in pretest weeks ( Figures 1, la, 2, 2a, 4, 4a, 6 and 6a). Additional blood samples are withdrawn for hematology and immunology evaluations twice in week 1 and once in weeks 2, 3 and 4. On days 30 and 31 necropsy and macroscopic examination of the tissues are performed. Tissue sections stained with hematoxylin and eosin are examined histologically from each animal. An oil red 0 section of the liver is examined from all animals on the study. Bone marrow brush smears are prepared at necropsy and evaluated.
• ESR Ervthrocvte sedimentation rate
• Pharmacological activity The pharmacological activities noted involved the hematopoietic system and the bone marrow. In general the effects were: IL-6 alone, an augmentation of platelets (Figs. 1 and la, Group I) ; G-CSF alone, or GM-CSF alone, an increase in neutrophils (Fig. 2, Group III and, respectively, Fig. 2a, Group II); and the combination of IL-6 + G-CSF, or of IL-6 + GM-CSF, an expansion of the platelets and neutrophils (Figs. 1 and 2, Group V and, respectively, Figs, la and 2a, Group IV).
• a further group of 3 patients receives rhIL-6 2.5 ⁇ g/kg/day once daily s.c. and concomitantly rhGM-CSF 5 ⁇ g/kg/day s.c. once daily, in the same treatment protocol as described in the preceding paragraph.
• CRP C-reactive protein
• Second clinical trial Two groups of 3 patients each undergoing autologous bone marrow transplantation receive 2.5 and, respectively, 5 ⁇ g/kg/day rhIL-6 once daily, as a bolus s.c. injection starting 2-4 hours after the infusion of the bone marrow, for 6 weeks or until recovery of a platelet concentration of 50 x 10 9 /1 for 3 days consecutively, and simultaneously, from day 1 to day 17 or 24, rhGM-CSF at 5 ⁇ g/kg/day once daily s.c.
• the serum concentration of CRP is determined as above under 1., twice weekly.

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