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]
  • A61K38/2013—IL-2
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis

Definitions

• interleukin 2 for treating spondylarthritis
• the present invention relates to administering interleukin 2 (IL-2) for use in treating spondylo arthritis. More specifically, the present invention relates to alleviating articular and extra-articular symptoms in patients with spondylo arthritis.
• IL-2 interleukin 2
• SpA Spondylarthritis
• SpA primarily affects the spine, although other joints can become involved. It causes inflammation of the spinal joints (vertebrae) that can lead to severe, chronic pain and discomfort. In the most advanced cases (but not in all cases), this inflammation can lead to new bone formation on the spine, causing the spine to fuse in a fixed, immobile position, sometimes creating a forward-stooped posture. This forward curvature of the spine is called kyphosis.
• SpA can also cause inflammation, pain and stiffness in other areas of the body such as the shoulders, hips, ribs, heels and small joints of the hands and feet.
• Extra-articular manifestations vary widely in terms of both frequency and severity. The most common extra-articular manifestations are represented by uveitis, bowel disease, heart, lung, skin, bone, kidney involvement and fatigue.
• SpA sacroiliac
• SpA is more common in men, but occurs in women as well.
• the severity of SpA varies greatly from person to person, and not everyone will experience the most serious complications or have spinal fusion. Some will experience only intermittent back pain and discomfort, but others will experience severe pain and stiffness over multiple areas of the body for long periods of time. AS can be very debilitating, and in some cases, lead to disability.
• NSAIDs nonsteroidal anti-inflammatory drugs
• Anti-TNFa in monotherapy or in combination with methotrexate, optionally with nonsteroidal anti-inflammatory drugs (NSAIDs) is used as second-line in case of intolerance or inefficacy of NSAIDs.
• the invention provides IL-2 for use in treating spondyloarthritis in a subject, wherein IL-2 is to be administered at a dose of about 1 to about 2MIU/day, wherein the treatment comprises at least a first course wherein interleukin-2 is administered once per day during at least 3 consecutive days, preferably during 3 to 7, still preferably during 4 to 5 consecutive days, preferably followed by a maintenance dose after 1 to 4 weeks.
• This dosage and regimen effectively activate Tregs without substantially activating Teffs.
• the consequence is a dramatic increase in the Treg/Teff balance in the subject, without impact on its immunocompetency.
• IL-2 is advantageously used in treating ankylosing spondylitis.
• IL-2 is useful for alleviating at least one articular symptom associated with spondyloarthritis, such as arthralgia or morning stiffness, and/or at least one extra-articular symptom associated with spondyloarthritis, such as uveitis.
• the "subject" or “patient” to be treated may be any mammal, preferably a human being.
• the human subject may be a child, an adult or an elder.
• the subject is a non-human mammal, such as cats, dogs, horses.
• the disease is often referred to "spondylosis deformans” or “cervical spondylosis deformans” in those non-human mammals.
• treating means any improvement in the disease. It includes alleviating at least one symptom, or reducing the severity or the development of the disease. In particular it includes reducing the risk, occurrence or severity of acute episodes (flares).
• the term “treating” or “treatment” encompasses reducing the progression of the disease. In particular the invention encompasses preventing or slowing down the progression of SpA.
• the term “treating” or “treatment” further encompasses prophylactic treatment, by reducing the risk or delaying the onset of the disease, especially in a subject who is asymptomatic but has been diagnosed as being "at risk”.
• the risk factors that predispose a person to SpA include:
• Tregs are T lymphocytes having immunosuppressive activity. Natural Tregs are characterized as CD4+CD25+Foxp3+ cells. Tregs play a major role in the control of inflammatory diseases, although their mode of action in such disease is not well understood. In fact, in most inflammatory diseases, Treg depletion exacerbates disease while Treg addition decreases it. Most Tregs are CD4+ cells, although there also exists a rare population of CD8+ Foxp3+ T lymphocytes with a suppressive activity.
• effector T cells designates conventional T lymphocytes other than Tregs (sometimes also referred to as Tconv in the literature), which express one or more T cell receptor (TCR) and perform effector functions (e.g., cytotoxic activity, cytokine secretion, anti-self recognition, etc).
• TCR T cell receptor
• Major populations of human Teff according to this invention include CD4+ T helper lymphocytes (e.g., ThO, Thl, Thl7) and CD4+ or CD8+ cytotoxic T lymphocytes, and they can be specific for self or non-self antigens.
• the present invention relates to administering interleukin 2 (IL-2) for use in treating spondyloarthritis. More specifically, the present invention relates to alleviating articular and extra-articular symptoms in patients with spondyloarthritis.
• IL-2 interleukin 2
• Sites of involvement include the spine, peripheral joints, and entheses (capsules, ligaments, and tendons).
• the present invention more particularly aims at preventing or alleviating inflammatory enthesiopathy progressing to ossification and ankylosis.
• Extra-articular symptoms include anterior uveitis, psoriasis or inflammatory bowel disease (IBD) and cardiovascular manifestations.
• IBD inflammatory bowel disease
• the present invention aims at preventing or alleviating articular symptoms in patients with spondylo arthritis who do not show uveitis, or in patients with spondyloarthritis who do not show any extra-articular symptom.
• Interleukin 2 (IL-2)
• IL-2 designates any source of IL-2, including mammalian sources such as e.g., human, mouse, rat, primate, and pig, and may be native or obtained by recombinant or synthetic techniques, including recombinant IL-2 polypeptides produced by microbial hosts.
• IL-2 may be or comprise the native polypeptide sequence, or can be an active variant of the native IL-2 polypeptide.
• the IL-2 polypeptide or active variant is derived from a human source, and includes recombinant human IL-2, particularly recombinant human IL-2 produced by microbial hosts.
• variants of IL-2 have been disclosed in the literature.
• Variants of the native IL-2 can be fragments, analogues, and derivatives thereof.
• fragment is intended a polypeptide comprising only a part of the intact polypeptide sequence.
• an “analogue” designates a polypeptide comprising the native polypeptide sequence with one or more amino acid substitutions, insertions, or deletions. Muteins and pseudopeptides are specific examples of analogues.
• Derivatives include any modified native IL-2 polypeptide or fragment or analogue thereof, such as glycosylated, phosphorylated, fused to another polypeptide or molecule, polymerized, etc., or through chemical or enzymatic modification or addition to improve the properties of IL-2 (e.g., stability, specificity, etc.).
• Active variants of a reference IL-2 polypeptide generally have at least 75%, preferably at least 85%, more preferably at least 90% amino acid sequence identity to the amino acid sequence of the reference IL-2 polypeptide.
• An active variant is, most preferably, a variant that activates Tregs.
• IL-2 variants are disclosed, for instance, in EP109748, EP136489, US4,752,585 ; EP200280, or EP 118617.
• a recombinant IL-2 i.e., an IL-2 that has been prepared by recombinant DNA techniques.
• the host organism used to express a recombinant DNA encoding IL-2 may be prokaryotic (a bacterium such as E. coli) or eukaryotic (e.g., a yeast, fungus, plant or mammalian cell). Processes for producing IL-2 have been described e.g., in US4,656,132; US4,748,234; US4,530,787; or US4,748,234, incorporated therein by reference.
• the invention uses an IL-2 of human origin, or an active variant thereof, more preferably produced recombinantly.
• a nucleotide and an amino acid sequence of human IL-2 are disclosed, for instance, in Genbank access number 3558 or P60568, respectively.
• the invention more preferably uses a human IL-2.
• IL-2 for use in the present invention is preferably in essentially pure form, e.g., at a purity of 95% or more, further preferably 96, 97, 98 or 99% pure.
• IL-2 is typically not combined or co-administered with a Teff suppressive agent.
• a Teff suppressive agent for use in the present invention, IL-2 is typically not combined or co-administered with a Teff suppressive agent.
• drug combinations may be contemplated.
• IL-2 may be used in monomeric or multimeric form.
• IL-2 is commercially available, including for pharmaceutical uses, and it is authorized for use in human patients. Suitable commercial forms include, e.g.,
• - Proleukin® (aldesleukin) is a recombinant unglycosylated des-alanyl-1, serine- 125 human inter leukin-2, produced in E.coli.
• Roncoleukin® is a recombinant human IL-2 produced in yeast.
• IL-2 as used in the present invention is des-alanyl-1, serine- 125 human inter leukin-2, preferably produced recombinantly. In a particular embodiment it is unglycosylated, preferably it is produced in E.coli.
• Interleukin-2 may be used alone or in combination with any other therapeutically active agent.
• IL-2 is administered at a dosage ranging from about 1 MlU/day to about 2 MlU/day. This dosage is particularly suitable for human subjects.
• This dosage effectively activates Tregs without substantially activating Teffs. The consequence is a dramatic increase in the Treg/Teff balance in the subject. At this dosage IL-2 substantially avoids side effects, while very substantially inducing Tregs.
• IL-2 is administered at a dose of 1 , 1.5 or 2 MlU/day.
• the treatment typically comprises at least a first course wherein interleukin-2 is administered once per day during at least 3 consecutive days, preferably during 3 to 7, still preferably during 4 to 5 consecutive days, preferably followed by a maintenance dose after 1 to 4 weeks.
• the maintenance dose is typically administered during at least one month, preferably at least about 3 months, still preferably at least about 6 months.
• the maintenance dose is administered between about 3 months and about 12 months, preferably between about 6 months and about 12 months.
• the maintenance treatment consists of an administration of interleukin-2 once or twice a week, every one or two weeks.
• the maintenance treatment consists of an administration of interleukin-2 once or twice a week, every one or two weeks, during a period of at least one month, preferably from about 3 months to about 12 months.
• the maintenance dosage is substantially the same as the first course dosage, or it can be a lower dosage.
• the treatment comprises at least a first course wherein interleukin- 2 is administered at a dosage of about 1 to about 2MIU/day, preferably 1-1.5 MlU/day once per day during 3 to 7 days, preferably 5 days, followed by a maintenance dose after two weeks, of about 1 to about 2MIU/day, preferably 1-1.5 MlU/day every 2 weeks, during at least three months, preferably at least six months.
• the subject is administered with IL-2 as the single active ingredient effective in treating spondylo arthritis.
• the subject it administered with IL-2, as well as with other active ingredients, either simultaneously or sequentially.
• the subject may be administered with IL-2 in combination with an anti-Tumor necrosis Factor (TNF) compound, especially anti-TNFa antibody, or methotrexate, and/or with nonsteroidal anti-inflammatory drugs (NSAIDs).
• TNF tumor necrosis Factor
• NSAIDs nonsteroidal anti-inflammatory drugs
• the dosage of such additional active ingredients can be reduced dramatically, reducing the risk and severity of side effects.
• 11-2 may be administered using any convenient route, including parenteral, e.g. intradermal, subcutaneous, or intranasal route.
• parenteral e.g. intradermal, subcutaneous, or intranasal route.
• the subcutaneous route is preferred.
• Oral, sublingual or buccal administrations are also encompassed.
• IL-2 is typically administered in association (e.g., in solution, suspension, or admixture) with a pharmaceutically acceptable vehicle, carrier or excipient.
• Suitable excipients include any isotonic solution, saline solution, buffered solution, slow release formulation, etc.
• Liquid, lyophilized, or spray-dried compositions comprising IL-2 or variants thereof are known in the art and may be prepared as aqueous or nonaqueous solutions or suspensions.
• the pharmaceutical compositions comprise appropriate stabilizing agents, buffering agents, bulking agents, or combinations.
• Inclusion criteria for study were as follows: 1) documented diagnosis of SpA according with AS AS criteria, 2) moderately active disease (30 ⁇ BASDAI ⁇ 60), 3) under standard treatment (> 2 months) at the time of inclusion (anti-TNFa in monotherapy or in combination with Methotrexate +/- NSAID).
• ASAS is Assessment of SpondyloArthritis International Society is intended for classification of both axial and peripheral SpA (Rudwaleit M, van der Heijde D, Landewe R et al. The assessment of SpondyloArthritis International Society classification criteria for peripheral spondyloarthritis and for spondylo arthritis in general. Ann. Rheum. Dis.70(l),25-31 (2011)).
• BASDAI Bit Ankylosing Spondylitis Disease Activity Index
• GARRETT et al A new approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. J Rheumatol 1994 21 (12) 2286-2291.
• Exclusion criteria included co-infection with HBV or HIV, several organ damages (heart failure, renal insufficiency, or hepatic insufficiency, or lung failure), pregnancy and drug addiction.
• Primary efficacy endpoint is the Treg response at Day-8. Secondary endpoints are:
• CGI-sev Clinical Global Impression severity scale
• CGI-eff Clinical Global Impression efficacy index
• BASDAI score 14/100
• Uveitis episodes have decreased in frequency and intensity.
• Patient describes also an increase of physical performance in sport activities. Due to this clinical improvement, the patient has stopped intake of NSAID.
• Patient 1-02-05-G-M (peripheral SpA, HLA-B27+) male, 65 years old. Regular treatment: with methotrexate and NSAID.
• BASDAI score 10/100
• ESR erythrocyte sedimentation rate
• BASDAI score 8.3/100
• the patient describes a clinical benefit under IL-2 therapy during 10 days after each IL-2 administration.
• Patient 2-02-06-L-A (peripheral SpA, HLA B27-) male, 43 years old.
• This patient has an initial clinical benefit manifested by resuming sport activity.
• Patient 1-07-01-C-D (axial and peripheral SpA, Takayasu disease and Ulcerative Colitis) female, 50 years old. Regular treatment: corticosteroids (7 mg/d), methotrexate (15 mg/w) and paracetamol (acetaminophen).
• the patient Under IL-2 therapy the patient has decreased BASDAI score (from 45.5/100 at baseline to 31/100 after 3 months of IL-2 therapy), notably due to decrease of arthralgia, asthenia and morning stiffness. The patient has stopped the intake of paracetamol.
• Patient 1-05-02-V-D (axial and peripheral SpA, HLA B27+, Behcet disease) male, 50 years old. Regular treatment: corticosteroids, colchicine, and analgesic drug.
• BASDAI score 19/100.

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• 2016
  • 2016-09-09 JP JP2018532806A patent/JP2018526459A/ja active Pending
  • 2016-09-09 EP EP16770224.0A patent/EP3347036A1/en not_active Withdrawn
  • 2016-09-09 US US15/758,800 patent/US20190060407A1/en not_active Abandoned
  • 2016-09-09 CA CA2997946A patent/CA2997946A1/en not_active Abandoned
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