WO2020007937A1 - Utilisation de l'interleukine-2 pour le traitement de la sclérose systémique - Google Patents

Utilisation de l'interleukine-2 pour le traitement de la sclérose systémique Download PDF

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WO2020007937A1
WO2020007937A1 PCT/EP2019/067898 EP2019067898W WO2020007937A1 WO 2020007937 A1 WO2020007937 A1 WO 2020007937A1 EP 2019067898 W EP2019067898 W EP 2019067898W WO 2020007937 A1 WO2020007937 A1 WO 2020007937A1
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interleukin
use according
systemic sclerosis
administered
human
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David Klatzmann
Roberta LORENZON
Arsène MEKINIAN
Michelle ROSENZWAJG
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Iltoo Pharma
Assistance Publique Hopitaux de Paris APHP
Sorbonne Universite
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Iltoo Pharma
Assistance Publique Hopitaux de Paris APHP
Sorbonne Universite
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin

Definitions

  • interleukin 2 for treating systemic sclerosis
  • the present invention relates to administering low dose interleukin 2 (IL-2) for use in treating systemic sclerosis.
  • IL-2 low dose interleukin 2
  • Systemic sclerosis also known as“scleroderma” is a rare and serious immune-mediated rheumatic disease that is characterized by fibrosis of the skin and internal organs and vasculopathy.
  • the early symptoms of the disease are often Raynaud’s phenomenon and gastro-oesophageal reflux in association with specific anti-nuclear antibody (ANA) profile.
  • Clinical manifestations include inflammatory skin disease (puffy and swollen fingers), skin fibrosis, ulcers, calcinosis, telangiectasia, musculoskeletal inflammation, or constitutional manifestations such as fatigue.
  • a subgroup of patients displays organ based manifestations of the disease, which might include lung fibrosis, pulmonary arterial hypertension, renal failure (usually with accelerated phase hypertension and a thrombotic microangiopathy clinical picture), or gastrointestinal complications.
  • Systemic sclerosis has a high mortality, greater than any other rheumatic disease.
  • the currently available treatments merely aim at reducing the complications of skin or internal organs (for a review, see Denton and Khanna, The Lancet, 2017, 390:1685- 1699) .
  • Treatment of skin-associated complications and interstitial lung disease consists in immune- modulating therapies (such as methotrexate, mycophenolate mofetil or cyclophosphamide).
  • Immuno- modulating therapies such as methotrexate, mycophenolate mofetil or cyclophosphamide.
  • Non-steroidal anti-inflammatory drugs and low-dose daily prednisolone may be helpful for musculoskeletal pain in association with intensive physiotherapy or occupational therapy.
  • Patients with a poor prognosis and lung fibrosis can receive intensive immunosuppression with haemopoietic autologous stem-cell transplantation (HSCT).
  • HSCT haemopoietic autologous stem-cell transplantation
  • Endothelin receptor antagonists may be used for controlling pulmonary arterial hypertension.
  • Use of ACE inhibitors in prevention of renal crisis is highly debated.
  • rituximab is being proposed as an alternative to cyclophosphamide for the treatment of interstitial lung diseases. Summary of the invention
  • the invention provides IL-2 for use in treating systemic sclerosis 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 2 or 3 consecutive days, preferably during 3 to 7, still preferably during 4 to 5 consecutive days, preferably followed by a maintenance dose after about six days or one week to about 4 weeks.
  • This dosage has been chosen to effectively expand and 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.
  • the Figure shows reduction of the Rodnan’s skin score in a patient with systemic sclerosis, treated with low dose IL-2 as described in the Example.
  • 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.
  • Systemic sclerosis is more frequent in women, but any gender is encompassed.
  • the patient may especially be an adult who is more than 30 or 40 years old.
  • the patients include patients affected with“Primary Systemic sclerosis”, with no other rheumatic disease, patients affected by “Sharp’s syndrome” (Mixed connective tissue disease (MCTD) disease with features of three diseases: lupus, scleroderma and polymyositis), and patients with “Reynolds syndrome” an association of Systemic sclerosis and primary biliary cirrhosis.
  • MCTD ixed connective tissue disease
  • the term“treating” or“treatment” 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 systemic sclerosis.
  • 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”.
  • 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 systemic sclerosis, including diffuse cutaneous systemic sclerosis or limited cutaneous systemic sclerosis.
  • IL-2 interleukin 2
  • cases of systemic sclerosis can generally be classified into one of two major disease subsets based on the extent of skin involvement: those with proximal involvement are classified as diffuse cutaneous systemic sclerosis, whereas those with restricted involvement affecting the limbs distal to the elbows or knees, with or without face and neck involvement, are classified as limited cutaneous systemic sclerosis.
  • These skin-based subsets define the disease dichotomously and have other distinguishing clinical associations, as well as specific serum autoantibody profiles.
  • the present invention relates to alleviating, delaying, slowing down or preventing development of articular and extra-articular symptoms, more particularly skin involvement, vascular manifestations (Raynaud’s phenomenon), organ failure, lung fibrosis, gastrointestinal manifestations, cardiac disease, pulmonary hypertension, and fatigue in patients with systemic sclerosis.
  • a method for treating articular symptoms of systemic sclerosis (such as arthralgia, puffy fingers or morning stiffness) in a patient in need thereof.
  • the present invention aims at preventing or alleviating articular symptoms in patients with systemic sclerosis, such as arthralgia, puffy fingers or morning stiffness.
  • the method provides preventing or alleviating skin involvement of systemic sclerosis, including skin thickening or hardening, which can be measured by a modified Rodnan skin score, as described e.g. in Khanna et al, Journal of Scleroderma and Related Disorders 2017“Standardizaton of the modifed Rodnan skin score for use in clinical trials of systemic sclerosis”.
  • measurement of skin thickening may also be used as a surrogate for disease activity.
  • Interleukin 2 (IL-2)
  • Interleukin-2 encompasses mammal wild type Interleukin-2, and variants thereof.
  • IL-2 is a human IL-2, or a variant thereof.
  • 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 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.).
  • the IL-2 moiety of active variants (including fragments, analogues, or derivatives) generally has at least 75%, preferably at least 80%, 85%, more preferably at least 90% or at least 95% amino acid sequence identity to the amino acid sequence of the reference IL-2 polypeptide, for instance mature wild type human IL-2.
  • An active variant is defined as a variant that shows an ability to stimulate Tregs, including variants with an improved ability, or a similar ability, or even a reduced ability to stimulate Tregs when compared to wild-type IL-2 or aldesleukin (as defined below), to the extent it does not stimulate Teffs more than it stimulates Tregs at the dosage herein defined.
  • Methods for testing whether a candidate molecule stimulate T cells, and Tregs in particular, are well- known. Variants may be tested for their ability to stimulate effector T cells (such as CD8+ T cells and NK cells) or CD4+Foxp3+ Tregs.
  • PBMC Total PBMC are activated (e.g. at 4x10 6 cells per well) with anti-CD3 antibody (e.g. at 100 ng/ml), and cultured. On day 3 of culture, cells are typically washed and rested in fresh media for 3 days. Cells are then washed and contacted with IL-2 variants (e.g. at either 10 nM or 100 pM). About three days later, cells are counted and analyzed by flow cytometry.
  • anti-CD3 antibody e.g. at 100 ng/ml
  • the IL-2 variant retains the capacity to stimulate, in Treg cells, STAT5 phosphorylation and/or phosphorylation of one or more of signaling molecules downstream of the IL-2R, e.g., p38, ERK, SYK and LCK.
  • the IL-2 variant retains the capacity to stimulate, in Treg cells, transcription or protein expression of genes or proteins, such as FOXP3 or IL-10, that are important for Treg cell survival, proliferation, activation and/or function.
  • the IL-2 variant exhibits a reduced capacity to stimulate endocytosis of IL- 2/IL-2R complexes on the surface of CD25+ T cells.
  • the IL-2 variant demonstrates inefficient, reduced, or absence of stimulation of PI3 -kinase signaling, such as inefficient, reduced or absent phosphorylation of AKT and/or mTOR (mammalian target of rapamycin).
  • the IL-2 variant retains the ability of wild type IL-2 to stimulate STAT5 phosphorylation and/or phosphorylation of one or more of signaling molecules downstream of the IL-2R in Treg cells, yet demonstrates inefficient, reduced, or absent phosphorylation of STAT5, AKT and/or mTOR or other signaling molecules downstream of the IL-2R in FOXP3- CD4+ or CD8+ T cells or NK cells.
  • the IL-2 variant is inefficient or incapable of stimulating survival, growth, activation and/or function of FOXP3- CD4+ or CD8+ T cells or NK cells.
  • these variants have the capacity to stimulate cell lines such as CTLL-2 or HT-2 which can be universally used to determined their biological activity.
  • wild type IL-2 means IL-2, whether native or recombinant, having the 133 normally occurring amino acid sequence of native human IL-2 (SEQ ID NO: 1, which is the IL-2 sequence less the signal peptide, consisting of an additional 20 N-terminal amino acids), whose amino acid sequence is described in Fujita, et. al, PNAS USA, 80,7437-7441 (1983).
  • IL-2 mutein means a polypeptide in which specific substitutions to the human mature interleukin-2 protein have been made.
  • IL-2 variants are disclosed, for instance, in EP109748, EP136489, US4,752,585 ; EP200280, EP118617, WO99/60128, EP2288372, US9,6l6,l05, US9,580,486,
  • certain mutations may result in a reduced affinity for the signaling chains of the IL-2 receptor (IL-2Rp/CD 122 and/or IL-2Ry/CDl32) and/or a reduced capacity to induce a signaling event from one or both subunits of the IL-2 receptor.
  • Other mutations may confer higher affinity for CD25 (IL-2Ra).
  • IL-2 muteins which show at least one amino acid substitution at position D20, N30, Y31, K35, V69, Q74, N88, V91, or Q126, numbered in accordance with wild type IL-2, meaning that the chosen amino acid is identified with reference to the position at which that amino acid normally occurs in the mature sequence of wild type IL-2 of SEQ ID NO:l.
  • Preferred IL-2 muteins comprise at least one substitution at position D20H, D20I, D20Y, N30S, Y31H, K35R, V69AP, Q74, N88R, N88D, N88G, N88I, V91K, or Q126L
  • amino acids belonging to one of the following groups represent conservative changes: -ala, pro, gly, gln, asn, ser, thr; -cys, ser, tyr, thr; -val, ile, leu, met, ala, phe; -lys, arg, his; -phe, tyr, trp, his ; and -asp, glu.
  • Variants with mutations which disrupt the binding to the a subunit of IL-2R are not preferred, as those mutants may have a reduced capacity to stimulate Tregs.
  • IL-2 can be produced by DNA recombinant technique.
  • 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, fimgus, plant or mammalian cell).
  • prokaryotic a bacterium such as E. coli
  • eukaryotic e.g., a yeast, fimgus, plant or mammalian cell.
  • Processes for producing IL-2 have been described e.g., in US4,656,l32; US4,748,234; US4,530,787; or US4,748,234, incorporated therein by reference.
  • IL-2 can be produced by chemical peptide synthesis.
  • IL-2 can be produced by the parallel synthesis of shorter peptides that are subsequently assembled to yield the complete sequence of IL-2 with the correct disulfide bridge.
  • a synthesis of Interleukin-2 is illustrated for instance in Asahina et al., Angewandte Chemie International Edition, 2015, Vol.54, Issue 28, 8226-8230, the disclosure of which being incorporated by reference herein.
  • IL-2 is a variant having at least 80%, preferably at least 90%, 95%, 98%, 99%, sequence identity with a mature wildtype human IL-2.
  • the variant can be glycosylated or non-glycosylated.
  • 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-l, serine- 125 human interleukin-2, produced in E.coli.
  • Roncoleukin® is a recombinant human IL-2 produced in yeast.
  • IL-2 is aldesleukin.
  • Aldesleukin is the active ingredient of Proleukin®.
  • Aldesleukin is an unglycosylated variant of mature human IL-2 comprising two amino acid modifications as compared to the sequence of mature human IL-2: the deletion of the first amino acid (alanine) and the substitution of cysteine at position 125 by serine.
  • amino acid sequence of aldesleukin is provided as SEQ ID NO: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.
  • the biological activity of IL-2 is typically determined in a standard cell proliferation assay using an IL-2 dependent cell line, such as CTLL-2 or HT-2.
  • the biological activity of IL-2 may be determined by a cell-based assay performed on HT-2 cell line (clone A5E, ATCC® CRL-1841TM) whose growth is dependent on IL-2. Cell growth in the presence of a range of test interleukin-2 product is compared with the growth recorded with IL-2 international standard (WHO 2nd International Standard for INTERLEUKIN 2 (Human, rDNA derived) NIBSC code: 86/500).
  • IL-2 as used in the present invention is des-alanyl-l, serine- 125 human interleukin-2, preferably produced recombinantly. In a particular embodiment it is unglycosylated, preferably it is produced in E.coli.
  • the IL-2 may be used alone or in combination with any other therapeutically active agent.
  • the IL-2 is conjugated to a water-soluble polymer, such as polyethylene glycol (PEG).
  • PEG polyethylene glycol
  • a preferred conjugate is described in patent application W02012/065086, wherein the conjugate comprises a water-soluble polymer such as PEG covalently attached via a releasable linkage to an amine group of an IL-2 moeity.
  • the IL-2 may be mutated at position D109C (with the C residue being capable of binding a PEG moiety), as described e.g. in international patent application W02016/0025385.
  • the IL-2 is fused to an immunoglobulin, preferably an IgG, preferably a human IgG, or preferably to a Fc region of an immunoglobulin.
  • an immunoglobulin preferably an IgG, preferably a human IgG, or preferably to a Fc region of an immunoglobulin.
  • a particular fusion construct that comprises two IL-2 proteins fused to one immunoglobulin, is disclosed e.g. in WO2014/023752 and WO2015/118016.
  • the IL-2 is fused at the N-terminal end of a Fc moiety, either directly or preferably through a peptide linker, e.g. an 8 to 12 amino acid linker, as described e.g. in international patent application WO2016/014428.
  • a peptide linker e.g. an 8 to 12 amino acid linker
  • the standard measure of an amount IL-2 is the International Unit (IU), which technically is not a fixed weight but the amount that produces a fixed biological effect in a specific cell proliferation assay, as determined by the World Health Organization (WHO).
  • IU International Unit
  • WHO World Health Organization
  • the principle of the International Unit is precisely to provide a standard to which any IL-2 molecule can be compared (regardless of their source, or their sequence, including wild-type or active variant sequences).
  • the WHO provide ampoules containing an IL-2 molecule that has been calibrated and serves as the reference to determine the dosage of a given preparation of IL-2 (again regardless of the source or sequence of said IL-2) defined by its potency.
  • the biological activity of the candidate IL-2 preparation is measured in a standard cell proliferation assay using an IL-2 dependent cell line, such as CTLL-2, and compared with the biological activity of the standard. The cells are grown in the presence of different doses of the standard.
  • a dose-response effect of IL-2 is established, where the dose of IL-2 is plotted on the X axis as IU and the measure of proliferation (pr) is on the Y axis.
  • the measure of proliferation pr
  • the product is used to grow the 11-2 dependent cells and the proliferation is measured.
  • the pr value is then plotted on the Y axis and from that value a line parallel to the X axis is drawn. From the point of intersection of this line with the dose response line, a line parallel to the Y axis is then drawn. Its intersection with the X axis provides the activity of the candidate IL-2 product in IU.
  • the lst standard (WHO international Standard coded 86/504, dated 1987) contained a purified glycosylated IL-2 derived from Jurkat cells and was arbitrarily assigned a potency of 100 IU/ampoule. As the stocks of the lst international standard (IS) were running low, the WHO had to replace it. The WHO provided another calibrated IL-2 ampoule, this time produced using E. coli.
  • the 2nd standard ampoules contained 210 IU of biological activity per ampoule. The change of standard ampoules does not mean that the IU changes. So, determining the dosage of a test IL-2 preparation will not vary whether one uses the lst standard ampoule or the 2nd standard ampoule, or a subsequent standard ampoule, as a reference.
  • IL-2 is preferably 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 about 2 or 3 consecutive days, preferably during 3 to 7, still preferably during 4 to 5 consecutive days, preferably followed by a maintenance dose after about six days or about 1 to about 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. In a preferred embodiment, 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, or every one or two weeks. In a preferred embodiment, 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 or higher dosage.
  • the treatment comprises at least a first course wherein interleukin- 2 is administered at a dosage of at most 3.5 MlU/day, preferably about 1 to about 2MIU/day, preferably 1-1.5 MlU/day, once per day during 2 or 3 to 7 days, preferably 5 days, followed by a maintenance dose after one to 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.
  • interleukin- 2 is administered at a dosage of at most 3.5 MlU/day, preferably about 1 to about 2MIU/day, preferably 1-1.5 MlU/day, once per day during 2 or 3 to 7 days, preferably 5 days, followed by a maintenance dose after one to 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 regimen is adjusted to the extent the Treg increase during maintenance remains at least 1.3, 1.5, 1.7, 1.9, or at least twice the baseline Treg level.
  • the regimen may be defined as a first (induction) course consisting of a dosage of at most 3.5MIU one per day during 1 to 3 days, followed by a maintenance course after 1 to 4 weeks.
  • the maintenance course then consists in an administration of IL-2 at a maintenance dosage, once every 2 weeks to once a month, during about 1 month, preferably 3 months, still preferably 6 months, or more.
  • the subject is administered with IL-2 as the single active ingredient effective in treating Systemic sclerosis.
  • 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 immunosuppressant agent (methotrexate, mycophenolate mofetil or cyclophosphamide), corticosteroids, and/or with nonsteroidal anti inflammatory drugs (NSAIDs), and/or optionally associated with at least another symptomatic drug that aims at reducing the complications of internal organs (e.g. ACE inhibitors to prevent renal crisis and endothelin receptor antagonists, epoprostenol analogues, and phosphodiesterase-5 inhibitors for pulmonary arterial hypertension).
  • the dosage of such additional active ingredients can be reduced dramatically, reducing the risk and severity of side effects.
  • Administration forms and routes 11-2 may be administered using any convenient route, including 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.
  • Exclusion criteria included co-infection with HBV or HIV, several organ damages (heart failure, renal crisis, or hepatic insufficiency, or pulmonary hypertension), pregnancy and drug addiction.
  • Each patient received 1MUI /day of aldesleukin from Day-l to Day-5 (the induction period), and then every 2 weeks from Day- 15 to Day- 180 (the maintenance period).
  • This protocol is referred to as“ldIL-2” (low dose IL-2) therapy. Patients are thereafter followed up for 2, 6 and 12 months.
  • 2-14-02-G-M Systemic Sclerosis with anti-centromere+ female, 72 years old without regular treatment. After three months of ldIL-2 therapy, muscular, articular and gastrointestinal symptoms (dysphagia) have decreased.
  • 2-14-06-RV (Reynolds Syndrome: Systemic Sclerosis with anti-centromere+ and primary biliary cirrhosis) female, 31 years old on regular treatment with hydroxychloroquine 400 mg/day. After three months of ldIL-2 therapy, the patient has dramatically decreased arthralgia.
  • 2-14-08-BP (Systemic Sclerosis with anti-centromere+) female, 54 years without regular treatment. Under ld IL-2 therapy, she dramatically improved skin involvement shown by a Rodnan’s score that decreasing from a value of 14 at baseline to a value of 5 after three and six months of therapy. See Figure.

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Abstract

L'invention concerne l'utilisation de l'interleukine-2 dans le traitement de la sclérose systémique chez un sujet, l'IL-2 devant être administrée à une faible dose inférieure à environ 3,5 MIU/jour.
PCT/EP2019/067898 2018-07-03 2019-07-03 Utilisation de l'interleukine-2 pour le traitement de la sclérose systémique Ceased WO2020007937A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023072877A1 (fr) * 2021-10-25 2023-05-04 Ellennbe Gmbh Composition pharmaceutique et kit comprenant une substance immuno-modulatrice pour traiter des maladies

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WO2016164937A2 (fr) 2015-04-10 2016-10-13 Amgen Inc. Mutéines de l'interleukine-2 pour l'expansion de lymphocytes t régulateurs
WO2017042370A1 (fr) * 2015-09-10 2017-03-16 Assistance Publique - Hôpitaux De Paris Utilisation d'interleukine 2 permettant de traiter la spondyloarthrite
WO2018089420A1 (fr) * 2016-11-08 2018-05-17 Delinia, Inc. Variants d'il-2 pour le traitement de maladies auto-immunes
WO2018218119A1 (fr) * 2017-05-25 2018-11-29 The Board Of Trustees Of The Leland Stanford Junior University Combinaison d'une faible dose d'il-2 et d'un inhibiteur de la désensibilisation treg il-2 r pour traiter des maladies inflammatoires auto-immunes et allergiques

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023072877A1 (fr) * 2021-10-25 2023-05-04 Ellennbe Gmbh Composition pharmaceutique et kit comprenant une substance immuno-modulatrice pour traiter des maladies

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