Methods of treating, inhibiting, or ameliorating an autoinflammatory disorder, disease, or condition in a subject in need thereof, comprising administering to a subject in need a therapeutic amount of an interleukin 1 (IL-1) antagonist, wherein the autoinflammatory disorder, disease, or condition is treated, inhibited, or ameliorated. The IL-1 antagonist is a molecule capable of binding and inhibiting IL-1. The therapeutic methods are useful for treating a human adult or child suffering from Neonatal Onset Multisystem Inflammatory Disorder (NOMID/CINCA), Muckle-Wells Syndrome (MWS), Familial Cold Autoinflammatory Syndrome (FCAS), familial mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS), or systemic onset juvenile idiopathic arthritis (Still's Disease).

Description of the Invention

BRIEF SUMMARY OF THE INVENTION

In a first aspect, the invention features a method of treating, inhibiting, or ameliorating an autoinflammatory disorder, comprising administering to a subject in need an interleukin 1 (IL-1) antagonist. An IL-1 antagonist is a compound capable of blocking or inhibiting the biological action of IL-1, including IL-1-binding fusion proteins. In a preferred embodiment, the IL-1 antagonist is an IL-1-specific fusion protein comprising two IL-1 receptor components and a multimerizing component, for example, an IL-1 fusion protein trap antagonist (an "IL-1 trap") described in U.S. patent publication No. 2003/0143697, published 31 Jul. 2003, herein specifically incorporated by reference in its entirety. In a specific embodiment, the IL-1 antagonist is the fusion protein shown in SEQ ID NO: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26. A preferred fusion protein is shown in SEQ ID NO:10. The invention encompasses the use of an IL-1-binding fusion protein substantially identical to the protein of SEQ ID NO: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, that is, a protein having at least 95% identity, at least 97% identity, at least 98% identity to the protein of SEQ ID NO: 4, 6, 8, 10,12, 14, 16, 18, 20, 22, 24, 26 and capable of binding and inhibiting IL-1. Further, in specific embodiments, the IL-1 antagonist is a fusion protein comprising one or more immunoglobulin-derived components in place of one or more receptor components. In specific embodiments, the IL-1 antagonist comprises one or more immunoglobulin-derived components specific for IL-1 and/or an IL-1 receptor.

The subject being treated is most preferably a human diagnosed as suffering from an autoinflammatory disorder. More specifically, the subject is a human adult or child diagnosed with an autoinflammatory disorder associated with mutations in CIAS-1, such as Neonatal Onset Multisystem Inflammatory Disorder (NOMID/CINCA), Muckle-Wells Syndrome (MWS), Familial Cold Autoinflammatory Syndrome (FCAS); familial Mediterranean fever (FMF); systemic onset juvenile idiopathic arthritis (Still's Disease), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), or Kawasaki Disease.

The method of the invention includes administration of the IL-1 antagonist by any means known to the art, for example, subcutaneous, intramuscular, intranasal, intravenous, transdermal administration or oral routes of administration. Preferably, administration is subcutaneous or intravenous.

In a second aspect, the invention features a method of treating, inhibiting, or ameliorating a disease or condition selected from the group consisting of NOMID/CINCA, MWS, FCAS, FMP, Still's Disease, TRAPS, and Kawasaki Disease, the method comprising administering to a subject in need an interleukin 1 (IL-1) antagonist. In a preferred embodiment, the IL-1 antagonist is a fusion protein capable of trapping IL-1. In a specific embodiment, the IL-1 antagonist is the fusion protein shown in SEQ ID NO: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, or a substantially identical protein capable of binding and inhibiting IL-1. A preferred IL-1 antagonist is shown in SEQ ID NO:10. Preferably, the subject treated is a child or adult human diagnosed with the disease or condition.

In a third aspect, the invention features a method of treating, inhibiting, or ameliorating Neonatal Onset Multisystem Inflammatory Disorder (NOMID/CINCA), comprising administering to a subject in need an interleukin 1 (IL-1) antagonist. In a preferred embodiment, the IL-1 antagonist is a fusion protein capable of trapping IL-1. In a specific embodiment, the IL-1 antagonist is the fusion protein shown in SEQ ID NO: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, or a substantially identical protein capable of binding and inhibiting IL-1. A preferred IL-1 antagonist is shown in SEQ ID NO:10.

In a fourth aspect, the invention features a method of treating, inhibiting, or ameliorating Muckle-Wells Syndrome (MWS), the method comprising administering to a subject in need an interleukin 1 (IL-1) antagonist. In a preferred embodiment, the IL-1 antagonist is a fusion protein capable of trapping IL-1. In a specific embodiment, the IL-1 antagonist is the fusion protein shown in SEQ ID NO: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, or a substantially identical protein capable of binding and inhibiting IL-1. A preferred IL-1 antagonist is shown in SEQ ID NO:10.

In a fifth aspect, the invention features a method of treating, inhibiting, or ameliorating Familial Cold Autoinflammatory Syndrome (FCAS) the method comprising administering to a subject in need an interleukin 1 (IL-1) antagonist. In a preferred embodiment, the IL-1 antagonist is a fusion protein capable of trapping IL-1. In a specific embodiment, the IL-1 antagonist is the fusion protein shown in SEQ ID NO: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, or a substantially identical protein capable of binding and inhibiting IL-1. A preferred IL-1 antagonist is shown in SEQ ID NO:10.

In a sixth aspect, the invention features a method of treating, inhibiting, or ameliorating familial mediterranean fever (FMF), the method comprising administering to a subject in need an interleukin 1 (IL-1) antagonist. In a preferred embodiment, the IL-1 antagonist is a fusion protein capable of trapping IL-1. In a specific embodiment, the IL-1 trap is the fusion protein shown in SEQ ID NO:4, 6, 8, 10,12, 14, 16, 18, 20, 22, 24, 26, or a substantially identical protein capable of binding and inhibiting IL-1. A preferred IL-1 trap is shown in SEQ ID NO:10.

In a seventh aspect, the invention features a method of treating, inhibiting, or ameliorating systemic onset juvenile idiopathic arthritis (Still's Disease), the method comprising administering to a subject in need an interleukin 1 (IL-1) antagonist. In a preferred embodiment, the IL-1 antagonist is a fusion protein capable of trapping IL-1. In a specific embodiment, the IL-1 antagonist is the fusion protein shown in SEQ ID NO: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, or a substantially identical protein capable of binding and inhibiting IL-1. A preferred IL-1 trap is shown in SEQ ID NO:10.

In an eighth aspect, the invention features a method of treating, inhibiting, or ameliorating tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), the method comprising administering to a subject in need an IL-1 antagonist. In a preferred embodiment, the IL-1 antagonist is a fusion protein capable of trapping IL-1. In a specific embodiment, the IL-1 antagonist is the fusion protein shown in SEQ ID NO: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, or a substantially identical protein capable of binding and inhibiting IL-1. A preferred IL-1 trap is shown in SEQ ID NO:10.

In specific embodiments of the therapeutic method of the invention, the subject is treated with a combination of a first IL-1-binding fusion protein trap molecule and a second therapeutic agent. The second therapeutic agent may be a second IL-1 antagonist, such as, for example, a second IL-1-binding fusion protein trap, anakinra (Kineret.RTM., Amgen), a recombinant, nonglycosylated form of the human IL-1 receptor antagonist (IL1Ra), or an anti-IL-18 drug such as IL-18BP or a derivative, an IL-18-binding fusion protein trap (an "IL-18 trap"), anti-IL-18, anti-IL-18RI, or anti-IL-18Racp antibodies or antibody fragments. Other co-therapies include low dose colchine for FMF, aspirin or other NSAIDs, steroids such as prednisolone, methotrexate, low dose cyclosporine A, TNF inhibitors such as Enbrel.RTM., or Humira.RTM., other inflammatory inhibitors such as inhibitors of caspase-1, p38, IKK1/2, CTLA-4Ig, anti-IL-6 or anti-IL6Ra, etc.

In a ninth aspect, the invention features a therapeutic method of treating an autoinflammatory disease or condition, comprising administering a pharmaceutical composition comprising an IL-1-binding fusion protein trap and a pharmaceutically acceptable carrier. In one embodiment, the IL-1-binding fusion protein trap is administered in a dose range of 1-20 mg/kg on a weekly basis for a treatment period of between 1 week to one year or more. In another embodiment, a total IL-1-binding fusion protein is administered in the range of 50-2000 mg, which may be provided in a single dose or in sequential doses over a period of time such as a period of weeks or months.

Other objects and advantages will become apparent from a review of the ensuing detailed description.

DETAILED DESCRIPTION

Before the present methods are described, it is to be understood that this invention is not limited to particular methods, and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only to the appended claims.

As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus for example, a reference to "a method" includes one or more methods, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference in their entirety.

General Description

Mutations in the gene CIAS1 are now recognized as being responsible for three rare genetic syndromes: Neonatal Onset Multisystem Inflammatory Disorder (NOMID), Muckle-Wells Syndrome (MWS), and Familial Cold Autoinflammatory Syndrome (FCAS). (Hoffman et al. 2001 Naure 29:301-305; Feldmann et al. 2002 Am J Hum Genet 71:198-203; Aksentijevich et al. 2002 Arthritis Rheum 46:3340-3348). In aggregate, these conditions are known as "CAPS", an acronym for "CIAS1 Associated Periodic Syndromes". CAPS disorders are exceedingly rare; with approximately 200-300 adults and children in the U.S. with FCAS and significantly fewer adults with NOMID or MWS known to have these conditions. The rarity of these conditions, particularly NOMID and MWS, are probably due to effects of disease severity on survival or reproductive fitness.

CAPS are inherited in an autosomal dominant manner, with a sporadic or familial pattern. CIAS1 encodes a protein called NALP3 that is a component of the "inflammasome", a subcellular enzyme complex that regulates the activity of caspase 1. Caspase 1 is the enzyme that cleaves the inactive pro-form of the proinflammatory cytokine, IL-1, into its biologically active form (Agostini et al. 2004 supra). Mutations in CIAS1 lead to increased production of IL-1 and numerous pathological consequences (Aksentijevich et al. 2002 supra). IL-1 strongly induces the production of acute phase reactants in the liver, such as C-reactive protein (CRP) and serum amyloid A (SAA).

The genetics of CAPS are interesting in that there can be a number of different point mutations in CIAS1 associated with these syndromes (Sarrauste de Menthiere et al. 2003 Nucleic Acids Res 31:282-285; Aksentijevich et al. 2002 supra). Some of these mutations are associated with only one syndrome; others two. For example, some mutations may be associated with FCAS as well as MWS; other mutations may be associated with MWS and NOMID. Approximately 50% of patients with NOMID do not have a recognized mutation in the coding region of CIAS1. In these patients, the disease may be due to an as-yet-unrecognized mutation in a regulatory region or protein of CIAS1, or in another gene encoding a closely-related protein in this pathway. FCAS is more genetically homogeneous than NOMID; almost all patients with FCAS share a common mutation (Sarrauste de Menthiere et al. 2003 supra; Hoffman et al. 2001 supra).

CAPS disorders share common clinical features and present as a spectrum of clinical severity. NOMID is the most seriously disabling, MWS somewhat less so and FCAS is the least severe. CAPS disorders have overlapping features and there are individuals and kindred with unique constellations of signs and symptoms. Features common to all these conditions include fevers, urticaria-like rash, arthritis or arthralgia, myalgia, malaise, and conjunctivitis. However, the spectrum of symptoms for any patient with a CAPS disorder may differ from that of another patient with the same disorder. A universal feature of active CAPS disease is laboratory test elevation of acute phase reactants, such as CRP, SAA, and/or erythrocyte sedimentation rate (ESR).

In NOMID, chronic aseptic meningitis may lead to mental retardation and these patients may also suffer disfiguring and disabling bony overgrowth at the epiphyses and patellae. These patients may also suffer blindness due to optic nerve atrophy that results from increased intracranial pressure. MWS and NOMID are commonly associated with severe inflammation that may include the auditory system, meninges, and joints. These patients may suffer daily high spiking fevers and a chronic rash that frequently changes in distribution and intensity. Patients may suffer hearing loss or deafness. Conjunctivitis and papilledema are frequently observed. Amyloidosis may develop and lead to renal failure due to chronic inflammation and overproduction of acute phase reactants (particularly SM). MWS is also known as "amyloidosis-deafness syndrome".

The clinical signs and symptoms of FCAS are induced by exposure to modestly cold air (e.g., seasonal temperature changes, air conditioning). Patients may have frequent (sometimes daily) episodes of a painful or pruritic rash, fever, fatigue, malaise, headache, nausea, and thirst during cold months or in locations where air conditioning is prevalent. In many locales, this may include most work places. FCAS is a source of frequent pain to patients and may restrict their employment, social, and recreational opportunities. Up to 2% of patients with FCAS develop amyloidosis, a life-threatening condition. This frequency is substantially higher than the rate of amyloidosis in the general community. The genetics and natural history of FCAS are described in detail Hoffman et al. 2001 Nature 29:301-305 and Hoffman et al. 2001 J Allergy din Immunol 108:615-620, which publications are herein specifically incorporated by reference in their entirety.

IL-1-Binding Fusion Protein Trap Antagonists

Interleukin-1 (IL-1) traps are multimers of fusion proteins containing IL-1 receptor components and a multimerizing component capable of interacting with the multimerizing component present in another fusion protein to form a higher order structure, such as a dimer. The IL-1-binding fusion proteins useful in the methods of the invention include two distinct receptor components that bind a single cytokine, resulting in the generation of antagonists with dramatically increased affinity over that offered by single component reagents. The IL-1-binding fusion protein traps are comprised of the extracellular domain of human IL-1R Type I (IL-1RI) or Type II (IL-1RII) followed by the extracellular domain of human IL-1 Accessory protein (IL-1AcP), followed by a multimerizing component. In a preferred embodiment, the multimerizing component is an immunoglobulin-derived domain, such as, for example, the Fc region of human IgG, including part of the hinge region, the CH2 and CH3 domains. An immunoglobulin-derived domain may be selected from any of the major classes of immunoglobulins, including IgA, IgD, IgE, IgG and IgM, and any subclass or isotype, e.g. IgG1, IgG2, IgG3 and IgG4; IgA-1 and IgA-2. Alternatively, the IL-1-binding fusion proteins useful in the method of the invention are comprised of the extracellular domain of human IL-1AcP, followed by the extracellular domain of human IL-1RI or IL-1RII, followed by a multimerizing component. For a more detailed description of the IL-1-binding fusion protein traps, see WO 00/18932, which publication is herein specifically incorporated by reference in its entirety. Preferred IL-1 antagonists have the amino acid sequence shown in SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26, or a substantially identical protein at least 95% identity to a sequence of SEQ ID NO: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, or 26, and capable of binding and inhibiting IL1.

Treatment Population

The therapeutic methods of the invention are useful for treating individuals affected with CIAS-1 mutation disorders (NOMID, MWS, FCAS), FMF, TRAPS, or Still's Disease. Commonly accepted diagnostic criteria for CIAS-1 mutation associated disease (NOMID, MWS, FCAS), Familial Mediterranean Fever, or Still's Disease (adult- or juvenile-onset) are know to those skilled in the art. In the case of patients diagnosed with FMF, the therapeutic method of the invention may be particularly useful for those with disease refractory to therapy with colchicine.

Methods of Administration

The invention provides methods of treatment comprising administering to a subject an effective amount of an agent of the invention. In a preferred aspect, the agent is substantially purified (e.g., substantially free from substances that limit its effect or produce undesired side-effects).

Various delivery systems are known and can be used to administer an agent of the invention, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the compound, receptor-mediated endocytosis (see, e.g., Wu and Wu, 1987, J. Biol. Chem. 262:4429-4432), construction of a nucleic acid as part of a retroviral or other vector, etc. Methods of introduction can be enteral or parenteral and include but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compounds may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local. In addition, it may be desirable to introduce the pharmaceutical compositions of the invention into the central nervous system by any suitable route, including intraventricular and intrathecal injection; intraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir. Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent.

In a specific embodiment, it may be desirable to administer the pharmaceutical compositions of the invention locally to the area in need of treatment; this may be achieved, for example, and not by way of limitation, by local infusion during surgery, topical application, e.g., by injection, by means of a catheter, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, fibers, commercial skin substitutes or angioplasty balloons or stents.

In another embodiment, the active agent can be delivered in a vesicle, in particular a liposome (see Langer (1990) Science 249:1527-1533). In yet another embodiment, the active agent can be delivered in a controlled release system. In one embodiment, a pump may be used (see Langer (1990) supra). In another embodiment, polymeric materials can be used (see Howard et al. (1989) J. Neurosurg. 71:105). In another embodiment where the active agent of the invention is a nucleic acid encoding a protein, the nucleic acid can be administered in vivo to promote expression of its encoded protein, by constructing it as part of an appropriate nucleic acid expression vector and administering it so that it becomes intracellular, e.g., by use of a retroviral vector (see, for example, U.S. Pat. No. 4,980,286), or by direct injection, or by use of microparticle bombardment (e.g., a gene gun; Biolistic, Dupont), or coating with lipids or cell-surface receptors or transfecting agents, or by administering it in linkage to a homeobox-like peptide which is known to enter the nucleus (see e.g., Joliot et al., 1991, Proc. Natl. Acad. Sci. USA 88:1864-1868), etc. Alternatively, a nucleic acid can be introduced intracellularly and incorporated within host cell DNA for expression, by homologous recombination.

Combination Therapies

In numerous embodiments, the IL-1 antagonists useful in the methods of the present invention may be administered in combination with one or more additional compounds or therapies. Combination therapy may be simultaneous or sequential. The IL-1-binding fusion proteins of the invention may be combined with, for example, TNF-inhibiting agents such as etanercept (Enbrel.RTM., Amgen), infliximab (Remicade.RTM., Centocor), Humira.RTM. (Abbott), thalidomide, steroids, anakinra (Kinaret.RTM., Amgen), or colchicine. Colchicine is a mainstay of therapy for subjects with FMF; in this study, subjects will not be removed from treatment with this medication. For Still's Disease (and classical autoinflammatory diseases), compounds such as methotrexate, cyclosporine, chlorambucil, cyclophosphamide (DMARDs) have been used as monotherapy or in combination with no consistent response. Some subjects respond to high doses of steroids. DMARDs, and more recently anti-TNF agents have been used with variable success. The IL-1-binding fusion proteins of the invention may also be combined with anti-IL-18 drugs, such as for example, IL-18BP or a derivative, an IL-18-binding fusion protein, anti-IL-18, anti-IL-18RI, or anti-IL-18Racp. Other co-therapies include low dose colchine for FMF, aspirin or other NSAIDs, steroids such as prednisolone, methotrexate, low dose cyclosporine A, TNF inhibitors such as Enbrel.RTM., or Humira.RTM., other inflammatory inhibitors such as inhibitors of caspase-1, p38, IKK1/2, CTLA4Ig, anti-IL-6 or anti-IL6Ra, etc.

Pharmaceutical Compositions

The present invention also provides pharmaceutical compositions. Such compositions comprise a therapeutically effective amount of an active agent, and a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly, in humans. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E. W. Martin.

In a preferred embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings. Where necessary, the composition may also include a solubilizing agent and a local anesthetic such as lidocaine to ease pain at the site of the injection. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.

The active agents of the invention can be formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with free amino groups such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with free carboxyl groups such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc.

The amount of the active agent of the invention which will be effective in the treatment of delayed-type hypersensitivity can be determined by standard clinical techniques based on the present description. In addition, in vitro assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the condition, and should be decided according to the judgment of the practitioner and each subject's circumstances. However, suitable dosage ranges for intravenous administration are generally up to about 2 grams of active compound. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

For systemic administration, a therapeutically effective dose can be estimated initially from in vitro assays. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC.sub.50 as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Initial dosages can also be estimated from in vivo data, e.g., animal models, using techniques that are well known in the art. One having ordinary skill in the art could readily optimize administration to humans based on animal data.

Dosage amount and interval may be adjusted individually to provide plasma levels of the compounds that are sufficient to maintain therapeutic effect. In cases of local administration or selective uptake, the effective local concentration of the compounds may not be related to plasma concentration. One having skill in the art will be able to optimize therapeutically effective local dosages without undue experimentation.

The amount of compound administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration, the frequency of administration and the judgment of the prescribing physician. The therapy may be repeated intermittently while symptoms are detectable or even when they are not detectable. The therapy may be provided alone or in combination with other drugs.

Kits

The invention also provides an article of manufacturing comprising packaging material and a pharmaceutical agent contained within the packaging material, wherein the pharmaceutical agent comprises at least one IL-1-specific fusion protein of the invention and wherein the packaging material comprises a label or package insert which indicates that the IL-1-specific fusion protein can be used for treating an autoinflammatory disease or condition.
 

Claim 1 of 6 Claims

1. A method of treating, inhibiting, or ameliorating an autoinflammatory disorder, disease, or condition in a subject in need thereof, comprising administering to the subject a therapeutic amount of an interleukin 1 (IL-1) fusion protein antagonist once a week, wherein the autoinflammatory disorder, disease, or condition is treated, inhibited, or ameliorated, wherein the IL-1 fusion protein antagonist comprises two IL-1 receptor components and a multimerizing component comprising the amino acid sequence of SEQ ID NO:10, wherein the subject is a human adult or child diagnosed with Neonatal Onset Multisystem Inflammatory Disorder (NOMID/CINCA), Muckle-Wells Syndrome (MWS), Familial Cold Autoinflammatory Syndrome (FCAS), familial mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS), or systemic onset juvenile idiopathic arthritis (Still's Disease).

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