Methods of treating, inhibiting, or ameliorating arthritis, including rheumatoid arthritis, osteoarthritis, psoriatic arthritis, ankylosing spondylitis, or juvenile rheumatoid arthritis, in a human subject in need thereof, comprising administering to a subject in need a therapeutic amount of an interleukin 1 (IL-1) antagonist, wherein arthritis inhibited, or ameliorated. The IL-1 antagonist is an IL-1-specific fusion protein comprising an IL-1 binding portion of the extracellular domain of human II-1RAcP, an IL-1 binding portion of the extracellular domain of human IL-1RI, and a multimerizing component antagonist, preferably comprising a sequence selected from the group consisting of SEQ ID NO:4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, or a substantially identical sequence.

Description of the Invention

SUMMARY OF THE INVENTION

In a first aspect, the invention features a method of treating, inhibiting, or ameliorating arthritis, 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 fusion proteins capable of trapping and blocking IL-1. In a preferred embodiment, the IL-1-specific fusion protein comprising two IL-1 receptor components and a multimerizing component, for example, an IL-1-specific fusion protein described in U.S. Pat. No. 6,472,179 and U.S. patent publication No. 2003/0143697, published 31 Jul. 2003, herein specifically incorporated by reference in their entirety. An IL-1-specific fusion protein comprises an IL-1 binding portion of the extracellular domain of human II-1RAcP, an IL-1 binding portion of the extracellular domain of human IL-1RI, and a multimerizing component. In a specific embodiment, the IL-1-specific fusion protein is the fusion protein shown in SEQ ID NO:4, 6, 8, 10, 12,14, 16, 18, 20, 22, 24, 26. In one preferred embodiment, the IL-1-specific fusion protein is SEQ ID NO:10. The invention encompasses the use of an IL-1-specific fusion protein substantially identical to the protein of SEQ ID NO:4, 6, 8, 10, 12,14, 16, 18, 20, 22, 24, or 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, or 26 and capable of binding and inhibiting IL-1. Further, in specific embodiments, the IL-1 antagonist is a modified IL-1-specific fusion protein comprising one or more receptor components and one or more immunoglobulin-derived components specific for IL-1 and/or an IL-1 receptor. In another embodiment, the IL-1 antagonist is a modified IL-1-specific fusion protein comprising 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 arthritis, including, but not limited to, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, ankylosing spondylitis, and juvenile rheumatoid arthritis, and other inflammatory arthritides, as well as other arthritidies in which inflammatory mediators plays a role. More specifically, the subject is a human adult or child diagnosed with arthritis. Methods for diagnosing the presence of arthritis are known in the art.

In a second aspect, the invention features a method of treating, inhibiting, or ameliorating osteoarthritis, comprising administering to a subject in need an interleukin 1 (IL-1) antagonist. The IL-1 antagonist useful in the methods of the invention is described above. The subject being treated is most preferably a human diagnosed as suffering from osteoarthritis.

In a third aspect, the invention features a therapeutic method of treating rheumatoid arthritis, comprising administering a pharmaceutical composition comprising an IL-1-specific fusion protein and a pharmaceutically acceptable carrier.

In a fifth aspect, the invention features a therapeutic method of treating psoriatic arthritis, comprising administering a pharmaceutical composition comprising an IL-1-specific fusion protein and a pharmaceutically acceptable carrier.

In a sixth aspect, the invention features a therapeutic method of treating ankylosing spondylitis, comprising administering a pharmaceutical composition comprising an IL-1-specific fusion protein and a pharmaceutically acceptable carrier.

In a seventh aspect, the invention features a therapeutic method of treating juvenile rheumatoid arthritis, comprising administering a pharmaceutical composition comprising an IL-1-specific fusion protein and a pharmaceutically acceptable carrier.

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

In specific embodiments of the therapeutic method of the invention, the subject is treated with a combination of an IL-1-specific fusion protein and a second therapeutic agent. The second therapeutic agent may be a second IL-1 antagonist such as a chimeric, humanized or human antibody to IL-1.alpha. or .beta. (such as CDP484, Celltech) or to the IL-1 receptor (for example, AMG-108, Amgen; R-1599, Roche), IL-1Ra (anakinra, Amgen; IL-1ra gene therapy, Orthogen), and ICE inhibitor, such as Vx-765 (Vertex), p38 MAP inhibitors, IKK 1/2 inhibitors (such as, UK436303, Pfizer; SPC-839, Serono/Signal), collagenase inhibitors (Periostat.TM., Collagenex), etc. The second therapeutic agent may also be selected from an anti-IL-18 compound, such as IL-18BP or a derivative, an IL-18-specific fusion protein (trap), anti-IL-18, anti-IL-18R1, or anti-IL-18R.beta.. Other co-therapies include low dose colchicine for FMF, aspirin or other NSAIDs, steroids such as prednisone, prednisolone, Depo-Medrol.TM. and Kenalog.TM.; and other disease modifying anti-rheumatic drugs (DMARDs) such as 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; and hyaluronic derivates such as Hyalgan.TM., Synvisc.TM., Orthovisc.TM., and Supartz.TM..

DETAILED DESCRIPTION OF THE INVENTION

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 by 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.

Rheumatoid Arthritis and Osteoarthritis

Rheumatoid arthritis (RA) is a chronic systemic disease characterized by progressive joint deformity and joint destruction in which cytokines play a central pathogenic role. The clinical course of RA is variable and often shows a remitting pattern. Three forms of RA can be distinguished: mild, self-limiting disease; mildly progressive disease; and aggressive disease which is difficult to control with medication, and is characterized by functional decline and radiologic deterioration of the joints, e.g., joint space narrowing and erosions. In accordance with the systemic nature of the disease, there are extra-articular manifestations which include vasculitis, alveolitis, and ocular disease. Prevalence of the disease as reported in the literature is approximately 1% of the U.S. population, with women accounting for two-thirds of all cases. The disease affects mainly adults but there is a juvenile form of rheumatoid arthritis (Chikanza et al (1998) J Pharm Pharmacol 50:357-69).

Onset of RA is often insidious with fatigue, anorexia, generalized weakness, and vague musculoskeletal symptoms. Specific symptoms appear later. Several joints, usually in a symmetrical fashion, are affected. Most often these are joints of the hands, wrists, knees, and feet. Joints are painful and swollen, and motion is limited. Morning stiffness of more than one hour is a very typical finding. With persistent inflammation, a variety of deformities develop which include most typically radial deviation of the wrist and hyperextension or flexion of the proximal interphalangeal joints; other deformities occur as well. Atrophy of skeletal muscle sets in. In approximately 20 to 30% of all patients, there is development of rheumatoid nodules on periarticular structures or sites of trauma, but they are usually of limited clinical significance. The nodules may be found in other structures such as the pleura or the meninges. Rheumatoid vasculitis can affect nearly all organ systems (lung, GI-tract, liver, spleen, pancreas, lymph nodes, testis, and the eye). Osteoporosis is common and may be aggravated by corticosteroids used in therapy (Lipsky (1998) Harrison's Textbook of Medicine 14.sup.th Ed. pp.1880-8).

Laboratory findings may include elevation of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) along with rheumatoid factor. Rheumatoid factor is an autoantibody against the Fc portion of IgG found in more than two-thirds of all patients. High titers of rheumatoid factor are a good indicator of disease activity. Mild anemia (normochromic, normocytic) and eosinophilia may be present as well. With progression of the disease, X-ray abnormalities such as general deformity, juxta-articular osteopenia, loss of articular cartilage, and bone erosion become more evident.

There is no curative treatment for RA. All drug regimens primarily attempt to relieve the symptoms and the inflammation. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) with a rapid onset of action are the first line of treatment. Selective COX-2 inhibitors such as Celebrex.RTM. and Vioxx.RTM. have been found to be better tolerated than regular NSAIDS which act both on COX-1 and COX-2. Oral glucocorticoids are added to the drug regimen if necessary. The third line of treatment includes disease modifying antirheumatic drugs (DMARDs); they have a slow onset of action, in some cases several months. DMARDs include azathioprine, sulphasalazine, gold, D-penicillamine, hydroxychloroquine, methotrexate, and cyclosporine. The most recent addition of etanercept/Enbrel.RTM. (chimeric TNF-receptor fusion protein) to the therapeutic armamentarium appears to be a successful step to improve patient treatment in a rational way. A second drug, infliximab/Remicade.RTM. (monoclonal anti-TNF antibody) has been approved for treatment of RA in combination with methotrexate. A third, IL-1ra (Antril.RTM.), a recombinant version of the naturally occurring IL-1 receptor antagonist, has been reported to have clinical benefit, as well (Bresnihan et al. (1998) Arthritis & Rheumatism 41:2196-2204; Campion et al. (1996) Arthritis & Rheumatism 39:1092-1101; Cohen et al. (1999) Arthritis & Rheumatism Abstracts 42(Supp):S273).

Osteoarthritis is the most common form of arthritis in Western populations (Jordan et al. (2003) Ann Rheum Dis. 62(12):1145-55). Knee OA, characterized clinically by pain and functional disability, is the leading cause of chronic disability among the elderly in the US. Risk factors for OA include age, gender, race, trauma, repetitive stress/joint overload, muscle weakness, and genetic factors.

Pathologically, the most striking changes in OA are focal loss of articular cartilage and marginal and central new bone formation. However, OA is not simply a disease of articular cartilage and the subchondral bone. Rather, it is a disease of the synovial joint, with alterations also found in the synovium, capsule, ligaments, periarticular muscle, and sensory nerves.

Although OA was once considered a non-inflammatory arthropathy, patients often present with signs and symptoms consistent with local inflammation and synovitis, and recent evidence from preclinical and clinical studies supports the role of inflammation and inflammatory mediators in its pathophysiology (Pelletier et al. (2001) Arthritis Rheum 44(6):1237-47). Both chondrocytes and synovium in OA can produce proinflammatory cytokines, including IL-1.beta., which can alter cartilage homeostasis in favor of cartilage degradation. For example, IL-1.beta. appears to be a major factor stimulating matrix metalloproteinase synthesis and other cartilage catabolic responses in OA. Thus, inflammation and inflammatory mediators may play a role in the joint destruction associated with OA as well as in pain.

Current treatment of osteoarthritis includes non-medicinal therapy, medicinal therapy, and surgical treatments. Non-medicinal treatments include exercise, thermal treatment, and assistive devices or bracing. For knee OA, range-of-motion and strengthening exercises are geared toward reduction of impairment, improvement of function, and joint protection. Medications include analgesics (e.g., acetaminophen), non-steroidal anti-inflammatory drugs (NSAIDS) that are either non-selective cyclooxygenase (COX) inhibitors or selective inhibitors of the COX-2 enzyme, injected intra-articular corticosteroids or viscosupplementation, and proven or putative disease-modifying osteoarthritis drugs (DMOADs). Surgical procedures include joint debridement and lavage, and lastly total knee arthroplasty.

The most commonly used medicinal treatments for knee OA typically provide less than 50% relief of pain. For example, use of acetaminophen, selective NSAIDs or non-selective NSAIDs typically results in mean improvements in knee OA pain of no more than 30 points from a baseline of .about.70 points using 100 point (100-mm) visual analog scales (Kivitz et al (2002) J Fam Pract 51(6):530-537). While this is a clinically important improvement, this indicates that there is substantial room for improvement in the pain management of knee OA. Further, no therapy has been demonstrated to retard the progression of structural degradation.

The pain and structural alterations of osteoarthritis are associated with inflammation and with alterations in inflammatory mediators, including IL-1. Hence, there is potential utility for agents that diminish the action of IL-1 in the treatment of both OA pain and OA disease (structural) modification. Indeed, a small, uncontrolled clinical study of intra-articularly administered IL-1 receptor antagonist, IL-1ra (anakinra), in knee osteoarthritis demonstrated a prolonged reduction in knee pain, supporting the potential of IL-1 inhibition as a therapeutic approach in treating OA (Goupille et al. (2003) Arthritis Rheum 48(suppl):S696). Although IL-1-specific fusion protein has not previously been studied in osteoarthritis, it has been shown to have anti-inflammatory activity associated with clinical effect in both animal models and humans in clinical trials.

IL-1-Specific Fusion Protein Antagonists

IL-1-specific fusion proteins (sometimes referred to as "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. Cytokine traps 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. In fact, the cytokine traps that are described herein are among the most potent cytokine blockers ever described. Briefly, the cytokine traps called IL-1 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 (II-1RAcP), followed by a multimerizing component. In one 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. For a more detailed description of the IL-1 traps, see WO 00/18932, which publication is herein specifically incorporated by reference in its entirety. Preferred IL-1-specific fusion proteins 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 IL-1.

In specific embodiments, the IL-1 antagonist comprises an antibody fragment capable of binding IL-1.alpha., IL-1.beta., IL-1R1 and/or II-1RAcP, or a fragment thereof. The preferred embodiment would be an antagonist of IL-1.beta.. One embodiment of an IL-1 antagonist comprising one or more antibody fragments, for example, single chain Fv (scFv), is described in U.S. Pat. No. 6,472,179, which publication is herein specifically incorporated by reference in its entirety. In all of the IL-1 antagonist embodiments comprising one or more antibody-derived components specific for IL-1 or an IL-1 receptor, the components may be arranged in a variety of configurations, e.g., a IL-1 receptor component(s)-scFv(s)-multimerizing component; IL-1 receptor component(s)-multimerizing component-scFv(s); scFv(s)-IL-1 receptor component(s)-multimerizing component, ScFv-ScFv-Fc, etc., so long as the molecule or multimer is capable of inhibiting the biological activity of IL-1.

Combination Therapies

In numerous embodiments, the IL-1 antagonists 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-specific fusion proteins of the invention may be combined with, for example, a chimeric, humanized or human antibody to IL-1.alpha. or .beta. (such as CDP-484, Celltech) or to the IL-1 receptor (for example, AMG-108, Amgen; R-1599, Roche), IL-1Ra (anakinra, Amgen; IL-1ra gene therapy, Orthogen), and ICE inhibitor, such as Vx-765 (Vertex), p38 MAP inhibitors, IKK 1/2 inhibitors (such as, UK-436303, Pfizer; SPC-839, Serono/Signal), collagenase inhibitors (Periostat.TM., Collagenex), etc. The second therapeutic agent may also be selected from an anti-IL-18 compound, such as IL-18BP or a derivative, an IL-18 trap, anti-IL-18, anti-IL-18R1, or anti-IL-18RAcP. Other co-therapies include low dose colchicine for FMF, aspirin or other NSAIDs, steroids such as prednisone, prednisolone, and other disease modifying anti-rheumatic drugs (DMARDs) such as 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; and hyaluronic derivates such as Hyalgan.TM. or Synvisc.TM..

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.
 

Claim 1 of 9 Claims

1. A method of treating, inhibiting, and/or ameliorating arthritis in a subject suffering therefrom, comprising administering to a subject in need a therapeutic amount of an interleukin 1 (IL-1) antagonist, wherein arthritis is treated, inhibited and/or ameliorated, wherein the IL-1 antagonist comprises the amino acid sequence of SEQ ID NO:10.

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