WO2006084145A2 - Procedes d'utilisation d'antagonistes il-1 afin de reduire la proteine c-reactive - Google Patents

Procedes d'utilisation d'antagonistes il-1 afin de reduire la proteine c-reactive Download PDF

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WO2006084145A2
WO2006084145A2 PCT/US2006/003866 US2006003866W WO2006084145A2 WO 2006084145 A2 WO2006084145 A2 WO 2006084145A2 US 2006003866 W US2006003866 W US 2006003866W WO 2006084145 A2 WO2006084145 A2 WO 2006084145A2
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crp
antagonist
mammal
protein
agent
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PCT/US2006/003866
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WO2006084145A3 (fr
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Steven P. Weinstein
Margaret Karow
Allen Radin
William Roberts
Li-Hsien Wang
Scott Mellis
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Regeneron Pharmaceuticals, Inc.
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Publication of WO2006084145A2 publication Critical patent/WO2006084145A2/fr
Publication of WO2006084145A3 publication Critical patent/WO2006084145A3/fr

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    • 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]
    • A61K38/2006—IL-1
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to methods of using interleukin-1 (IL-1) antagonists to reduce C- reactive Protein (CRP) in a subject in need thereof.
  • IL-1 interleukin-1
  • the invention also relates to methods of reducing the risk of or ameliorating a condition associated with elevated CRP, including, for example, atherosclerosis in a human subject by administrating an IL-1 antagonist.
  • the invention further relates to methods of reducing the risk of adverse events in a subject undergoing or who has undergone a medical procedure such as vein grafts, angioplasty, etc.
  • Coronary artery disease continues to be a leading cause of death in Western societies, despite major advances in the prevention, detection, and treatment of the disease.
  • Most presentations of acute myocardial ischemia are unheralded - only 20% of acute coronary attacks are preceded by longstanding, stable angina pectoris.
  • Acute coronary syndrome (ACS), an umbrella term used to describe clinical symptoms consistent with unexpected or atypically severe and prolonged acute myocardial ischemia, includes unstable angina (UA) and acute myocardial infarction (AMI).
  • ACS is a major cause of emergency medical care and hospitalization in the U.S.
  • Interleukin-1 (IL-1) traps are multimers of fusion proteins containing IL-1 receptor components and a multimerizing component capable of interacting another fusion protein to form a higher order structure, such as a dimer.
  • IL-1 traps are described in WO 00/18932.
  • the IL-1 trap has been developed as an antagonist of IL-1 in the treatment of rheumatoid arthritis and other inflammatory diseases.
  • a key role of inflammatory mechanisms in the pathogenesis of atherosclerosis and its complications has been recognized and supported by basic and clinical research over the past decade.
  • the invention features a method of reducing C-reactive protein (CRP) in a human subject, comprising administering to the subject an interleukin 1 (IL-1) antagonist such that CRP is reduced. More specifically, the invention features a method of reducing plasma/serum CRP levels in a human subject, comprising administering to the subject an inteFfeiikiA 1" (Ifcp1 : !) yH agbnist »r ⁇ at CRP is reduced relative to pretreatment level.
  • An IL-1 antagonist is a compound capable of blocking or inhibiting the biological action of IL-1 , including fusion proteins capable of trapping IL-1 , such as an IL-1 trap.
  • the IL-1 trap is an IL-1-specific fusion protein comprising two IL-1 receptor components and a multimerizing component, for example, an IL-1 trap described in U.S. patent publication No. 2003/0143697, published 31 July 2003.
  • An IL-1 trap fusion protein comprises an IL-1 binding portion of the extracellular domain of human IL-I RAcP, an IL-1 binding portion of the extracellular domain of human IL-1 Rl, and a multimerizing component.
  • the IL-1 trap is the fusion protein shown in SEQ ID NO:2, encoded by the nucleic acid sequence of SEQ ID NO:1.
  • the invention encompasses the use of an IL-1 trap substantially identical to the protein of SEQ ID NO:2, that is, a protein having at least 95% identity, at least 97% identity, at least 98% identity to the protein of SEQ ID NO:2 and capable of binding and inhibiting IL-1.
  • the IL-1 antagonist is a modified IL- 1 trap comprising one or more receptor components and one or more immunoglobulin-derived components specific for IL-1 and/or an IL-1 receptor.
  • the IL-1 antagonist is a modified IL-1 trap comprising one or more immunoglobulin-derived components specific for IL-1 and/or an IL-1 receptor.
  • the methods of the invention may be carried out with an IL-1 antagonist such as a chimeric, humanized or human antibody to IL-1 ⁇ or ⁇ (such as CDP-484, Celltech) or to the IL-1 receptor (for example, AMG-108, Amgen; R-1599, Roche), IL-I Ra (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), and collagenase inhibitors (PERIOSTATTM, Collagenex).
  • an IL-1 antagonist such as a chimeric, humanized or human antibody to IL-1 ⁇ or ⁇ (such as CDP-484, Celltech) or to the IL-1 receptor (for example, AMG-108, Amgen; R-1599, Roche), IL-I Ra (anakinra, Amgen; IL-1ra
  • the method of the invention carried out with an IL-1 trap is capable of rapidly reducing CRP levels in a human subject.
  • reducing CRP level is meant a reduction of at least 20%, more preferably at least 30%, even more preferably at least 40%, still more preferably at least 50%, at least 60%, at least 70%, or at least 80% relative to pretreatment level.
  • Reduction of CRP level may be determined by a reduction relative to pretreatment level, e.g., reducing CRP level in a subject with elevated CRP level by e.g., 50% relative to pre-treatment level.
  • Achieving a reduction in CRP level in an individual may be determined by, for example, measuring a reduction from pre-treatment level or by achieving a target or normal level with treatment as defined by current medical guidelines.
  • Reduction in CRP levels achieved rapidly upon administration of said IL-1 antagonist e.g., within about 1-10 days, preferably in 7 days or less, 6 days or less, 5 days or less, 4 days or less, 3 days or less, 2 days or less, or even within 24 hrs following treatment.
  • a subject suitable for treatment by the method of the invention is a subject at risk for development or recurrence of a condition or an adverse medical event associated with elevated CRP, such as, in non-limiting examples, atherosclerosis, acute colfo ⁇ aryi's ⁇ niyi- ⁇ Mel'str ⁇ Kyi-W ⁇ p ⁇ cilic embodiments, the subject at risk has an elevated serum CRP level, e.g., as determined by expert consensus guidelines at the time of treatment.
  • a person at risk for development or recurrence of a condition associated with elevated CRP has a serum CRP level of ⁇ 1.0 mg/L.
  • a person at risk for development or recurrence of a condition associated with elevated CRP has a serum/plasma CRP level of > 2.0 mg/L; > 2.5 mg/L; ⁇ 3.0 mg/L (CDC-AHA guidelines); > 3.5 mg/L; or ⁇ 4.0mg/L.
  • a preferred subject for treatment by the methods of the invention is a subject who will undergo or has undergone a medical procedure associated with risk of adverse medical event, for example, a subject undergoing a revascularization procedure, such as angioplasty, coronary artery bypass graft (CABG), vascular stenting, vein graft, prosthetic graft, or a similar procedure.
  • a subject may have a normal serum CRP level or an elevated serum CRP level.
  • a preferred subject for treatment by the methods of the invention is a subject suffering from or at risk of suffering from a condition which is ameliorated, inhibited, or reduced by a reduction in serum/plasma CRP level.
  • Conditions characterized by elevated C-reactive protein include, for example, atherosclerosis, including coronary artery disease, cerebral vascular disease, peripheral vascular disease, an infection or an allergic complication resulting from an infection, an inflammatory disease, necrosis, trauma, and/or a malignancy.
  • the methods of the invention include administration of the IL-1 antagonist by any means known to the art, for example, subcutaneous, intramuscular, intravenous, topical, transdermal or oral routes of administration.
  • administration is by subcutaneous or intravenous injection or infusion.
  • the method of the invention may encompass a single administration of an IL-1 antagonist, or it may encompass multiple administrations of the IL-1 antagonist. Multiple administrations may include a frequency that is weekly, bi-weekly, monthly, bi-monthly, or quarterly, depending on the condition being treated and/or result desired.
  • the IL-1 antagonist is initially administered prior to initiation of a medical procedure such as angioplasty, or initial administration may be simultaneous or following the medical procedure.
  • an IL-1 antagonist administered will depend on the condition being treated, the agent utilized, the desired result, and/or the presence of secondary therapeutic agents.
  • the IL-1 antagonist administered is an IL-trap, for example, as exemplified by the protein of SEQ ID NO:2, a therapeutically effective dose will depend on whether single or multiple doses are given, as well as frequency of administration. Doses may range from about 20 to about 2000 mg protein of IL-1 trap, or 50-2000 mg, 50-500 mg, or 50-350 mg.
  • the subject is triiy v h' . ⁇ ttii) t rap and a second therapeutic agent.
  • the second therapeutic agent may be one or more of a second IL-1 antagonist, such as, for example, anakinra (KINERET®, Amgen), a recombinant, nonglycosylated form of the human IL-1 receptor antagonist (ILI Ra), or an anti-IL-18 drug such as IL-18BP or a derivative, an IL-18- binding fusion protein (IL-18 "trap"), anti-IL-18, anti-IL-18R1 , or anti-IL-18RAcP.
  • a second IL-1 antagonist such as, for example, anakinra (KINERET®, Amgen), a recombinant, nonglycosylated form of the human IL-1 receptor antagonist (ILI Ra), or an anti-IL-18 drug such as IL-18BP or a derivative, an IL-18- binding fusion protein (IL-18 "trap"), anti-IL-18, anti-IL-18R1 , or anti-IL-18RAcP.
  • a second IL-1 antagonist such as, for example, anakinr
  • co- therapies include low dose colchicine for FMF, anti-platelet agents (such as aspirin or clopidogrel (PLAVIXTM, Sanofi-Aventis) or other NSAIDs, anti-ischemic (such as nitroglycerin or beta blockers), anti-thrombin such as heparin, hirudin, bivlarudin, fibrinolytic agents, GPIIb/llla antagonists (abciximab, eptifibatide, tirofiban) steroids such as prednisone, prednisolone, methotrexate, low dose cyclosporine A, folate, TNF inhibitors such as etanercept (ENBREL®), or adalimubab (HUMIRA®), other inflammatory inhibitors such as inhibitors of caspase-1 , p38 MAP kinase, IKK1/2, CTLA-4lg, anti-IL-6 or anti-IL6Ra, etc.
  • anti-platelet agents such
  • a second agent may include a cholesterol-lowering agent such as hydroxymethylglutaryl-CoA reductase inhibitors (statins), vitamin E and derivatives thereof, and fish oil (Chan et al. (2002) supra).
  • secondary agents may include insulin sensitizers.
  • the method of the invention may also be combined with lifestyle changes to reduce risk of development or recurrence of an undesirable conditions, for example, reduction of CRP may be achieved with a combination of an IL-1 antagonist and exercise, weight loss, reduction of alcohol intake, or improved control of a condition such as diabetes.
  • the invention features a method of reducing C-reactive protein (CRP) in a human subject, comprising administering to the subject an interleukin 1 (IL-1) antagonist such that CRP is reduced, wherein the IL-1 antagonist is an IL-1 -specific fusion protein (IL-1 "trap”) as described above.
  • IL-1 interleukin 1
  • the invention features a method of treating, inhibiting, or ameliorating or reducing the risk of suffering from atherosclerosis, comprising administering to a subject in need an interleukin 1 (IL-1) antagonist.
  • atherosclerosis includes coronary artery disease, cerebral vascular disease, and/or peripheral vascular disease.
  • the invention features a method of treating, inhibiting, or ameliorating or reducing the risk of development or recurrence of acute coronary syndrome (ACS), comprising administering to a subject in need an interleukin 1 (IL-1) antagonist.
  • ACS acute coronary syndrome
  • the invention features a method of treating, inhibiting, or ameliorating angina, comprising administering to a subject in need an interleukin 1 (IL-1) antagonist.
  • the invention features a method of treating, inhibiting, or ameliorating or reducing the risk of suffering a myocardial infarction, comprising administering to a subject in need an interleukin 1 (IL-1) antagonist.
  • the myocardial infarction may be non-ST-segment elevation myocardial infarction (NSTEMI), ST-segment elevation myocardial infarction (STEMI), Q-wave elevation myocardial infarction, non-Q-wave elevation myocardial infarction.
  • the invention features the use of an interleukin-1 (IL-1) antagonist in the prd ⁇ a n f teafiigiilffi ed Bcing C-reactive protein (CRP) in a mammal.
  • IL-1 interleukin-1
  • CRP C-reactive protein
  • Fig. 1 is a graph showing median percent change from baseline CRP in RA subjects treated with placebo ( ⁇ ), 25 mg ( ⁇ ), 50 mg (A), or 100 (x) mg IL-1 trap.
  • Atherosclerosis is recognized as a chronic inflammatory process (Ross (1999) Am Heart J. 138:S419-20). Studies have shown that increased plasma concentrations of high-sensitivity C-reactive protein (hs-CRP or CRP), a sensitive marker for low-grade inflammation, are associated with increased risk of cardiovascular events (Rifai et al. (2001) Clin Chem 47:403-11 ; Taubes (2002) Science 296:242-245). CRP can be measured in the serum or plasma. CRP is released by the body in response to acute injury, infection or other inflammation-inducing conditions, such as atherosclerosis.
  • hs-CRP or CRP high-sensitivity C-reactive protein
  • CRP concentrations are also associated with obesity and a cluster of metabolic risk factors related to visceral obesity, such as hyperinsulinemia, hypertriglycridemia, and low high density lipoprotein (HDL)
  • hyperinsulinemia hypertriglycridemia
  • HDL low high density lipoprotein
  • AgiMlWlth l HonddfiHiaiiiMIcliariisms which reduce CRP have been described (for example, Vx-702, Vertex).
  • LDL low density lipoprotein
  • Too much cholesterol or LDL-cholesterol in the bloodstream is typically a major risk factor for cardiovascular disease.
  • excessive cholesterol can lead to formation of atheroscleromatous plaques. These plaques can cause narrowing and hardening of the arteries (i.e., atherosclerosis), which can impede blood flow and lead to a heart attack or stroke.
  • statins generally alter the metabolism of various constituents within the cholesterol metabolic pathway.
  • statins are associated with numerous side effects, including elevation of plasma triglycerides, increased liver aminotransferase activity, abdominal discomfort, nausea, vomiting, diarrhea, malaise, QT interval prolongation, decreased high- density lipoprotein levels, and risk of rhabdomyolysis.
  • Elevated CRP levels are also associated with a wide variety of diseases, including, for example, chemodialysis, surgery, sickle cell anemia, diabetes, obesity, hypofibrinolysis, multiple organ failure, and heart transplant.
  • Treatment strategies in patients with stable angina include lifestyle modification and drug therapy for risk factor modification (obesity, tobacco use, dyslipidemia, hypertension, metabolic syndrome), ACE inhibition, beta-adrenergic receptor blockade, aspirin, and angiographically directed revascularization.
  • Treatment strategies in UA/NSTEMI include antiplatelet therapies such as aspirin, thienopyridine (ticlopidine, clopidogrel, platelet glycoprotein llb/llla antagonists), anticoagulants, lipid risk factor modification, and angiographically directed revascularization. Both clopidogrel and abciximab modestly suppress the rise in circulating inflammatory markers after PCI.
  • Autoinflammatory diseases are illnesses characterized by episodes of inflammation that, u n ff ⁇ " a ⁇ Of fr?r? ⁇ S ⁇ h S-M t ⁇ 'rciy irS3 * iEy%:kl»U : fe production of high titer autoantibodies or antigen-specific T cells.
  • IL-1 plays a pathogenic role in several of these diseases.
  • Autoinflammatory disorders include, for example, Neonatal Onset Multisystem Inflammatory Disease (NOMID), Muckle-Wells Syndrome (MWS), and Familial Cold Autoinflammatory Syndrome (FCAS), Familial Mediterranean Fever (FMF), and adult Still's disease.
  • FMF is associated with mutations in pyrin encoding MEFV.
  • NOMID, MWS and FCAS are associated with mutations in cryopyrin-encoding CIAS1.
  • the methods of the invention are advantageously used with a subject who is to undergo or has undergone a medical procedure such as angioplasty, vascular stenting, vein graft (such as CABG or peripheral vein graft), dialysis, etc. Many of these procedures are known to cause an increase or a further increase in CRP levels, and are believed to place the subject at risk for an adverse medical event, e.g., such as a myocardial infarction.
  • a medical procedure such as angioplasty, vascular stenting, vein graft (such as CABG or peripheral vein graft), dialysis, etc.
  • Many of these procedures are known to cause an increase or a further increase in CRP levels, and are believed to place the subject at risk for an adverse medical event, e.g., such as a myocardial infarction.
  • blocker By the term “blocker”, “inhibitor”, or “antagonist” is meant a substance that retards or prevents a chemical or physiological reaction or response. Common blockers or inhibitors include but are not limited to antisense molecules, antibodies, antagonists and their derivatives. More specifically, an example of an IL-1 blocker or inhibitor is an IL-1 antagonist including, but not limited to, an IL-1-binding fusion protein (an IL-1 "trap”) which binds and inhibits IL-1. [0037] By the term “therapeutically effective dose” is meant a dose that produces the desired effect for which it is administered.
  • substantially identical is meant a protein sequence having at least 95% identity to an amino acid sequence of SEQ ID NO:2, and capable of binding IL-1 and inhibiting the biological activity of IL-1.
  • identity or "homology” is construed to mean the percentage of amino acid residues in the candidate sequence that are identical with the residue of a corresponding sequence to which it is compared, after aligning the sequences and introducing gaps, if necessary to achieve the maximum percent identity for the entire sequence, and not considering any conservative substitutions as part of the sequence identity. Neither N- or C-terminal extensions nor insertions will be construed as reducing identity or homology. Methods and computer programs for the alignment are well known in the art. Sequence identity may be measured using sequence analysis software (e.g., Sequence Analysis Software Package, Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Ave., Madison, Wis. 53705). This software matches similar sequences by assigning degrees of and other modifications.
  • sequence analysis software e.g., Sequence Analysis Software Package, Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Ave., Madison, Wis. 53705
  • lnterleukin-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.
  • Cytokine traps are a novel extension of the receptor-Fc fusion concept in that they 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 cytokine traps that are described herein are among the most potent cytokine blockers ever described.
  • the cytokine traps called IL-1 traps are comprised of the extracellular domain of human IL-1 R Type I (IL-1 Rl) or Type Il (IL-1 RII) followed by the extracellular domain of human IL-1 Accessory protein (IL-IAcP), followed by a multimerizing component.
  • 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 1 IgD, IgE, IgG and IgM, and any subclass or isotype, e.g. IgGI , lgG2, lgG3 and lgG4; lgA-1 and lgA-2.
  • the IL-1 traps are comprised of the extracellular domain of human IL-IAcP, followed by the extracellular domain of human IL-1 Rl or IL-1 RII, followed by a multimerizing component.
  • the IL-1 trap is the amino acid sequence shown in SEQ ID NO:2, or a substantially identical protein at least 95% identity to a sequence of SEQ ID NO:2 and capable of binding and inhibiting ILL
  • the IL-1 antagonist comprises an antibody fragment capable of binding IL-1 ⁇ , IL-1 ⁇ , IL-1 R1 and/or IL-1 RAcp, or a fragment thereof.
  • the preferred embodiment is an antagonist of IL-1 ⁇ .
  • an IL-1 antagonist comprising one or more antibody fragments, for example, single chain Fv (scFv), is described in U.S. 6,472,179.
  • 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.
  • populations of human subjects which are preferably treated by the methods of the invention include a subject determined to be at risk for development or recurrence of a condition or adverse medical event, which condition may be ameliorated, redifcIcu i i t y ,re c$ ⁇ S B Serum/plasma CRP levels.
  • a subject preferably treated by the methods of the invention is a subject exhibiting an elevated serum/plasma CRP level which places that subject at risk for development or recurrence of a condition associated with elevated serum/plasma CRP levels.
  • the subject to be treated by the methods of the invention is a subject who is to undergo or has undergone a medical procedure associated with risk of an adverse medical event, such as, in non-limiting examples, may be a medical procedure such as angioplasty, CABG, stenting, vein graft, or a similar procedure.
  • the subject being treated is a human diagnosed as suffering from or at risk for suffering from a condition characterized by elevated C-reactive protein (Pepys et al. (2003) J Clin Invest 111 :1805-1812).
  • C-reactive protein Pepys et al. (2003) J Clin Invest 111 :1805-1812.
  • atherosclerosis including coronary artery disease, cerebral vascular disease, pheripheral vascular disease, an infection or an allergic complication resulting from an infection, an inflammatory disease, necrosis, trauma, and/or a malignancy.
  • Coronary artery disease includes such conditions as, for example, acute coronary syndrome (ACS), myocardial ischemia, unstable angina, acute myocardial infarction, ST elevation myocardial infarction, non-ST elevation myocardial infarction, Q-wave myocardial infarction, non-Q-wave myocardial infarction.
  • An infection may be bacterial, systemic or severe fungal, mycobacterial, or viral. Allergic complications resulting from infection include, for example, rheumatic fever or erythema nodosum.
  • Inflammatory diseases include rheumatoid arthritis, juvenile chronic arthritis, ankylosing spondylitis, psoriatic arthritis, systemic vasculitis, polymyalgia rheumatica, Reiter disease, Crohn's disease, and/or Familial Mediterranean disease.
  • Necrosis includes myocardial infarction, tumor embolization, and acute pancreatitis. Trauma may result from surgery, burns and/or fractures.
  • Malignancy includes lymphoma, carcinoma and sarcoma.
  • 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.
  • An IL-1 antagonist may be combined with, for example, TNF-inhibiting agents such as etanercept (ENBREL®, Amgen), infliximab (REMICADE®, Centocor), adalimuab (HUMIRA®, Abbott), thalidomide and thalidomide-related compounds, steroids, anakinra (KINARET®, Amgen), colchicine, methotrexate, cyclosporine, chlorambucil, cyclophosphamide, prednisolone, anti-IL-6 or anti-IL6Ra, and sulfasalazine.
  • TNF-inhibiting agents such as etanercept (ENBREL®, Amgen), infliximab (REMICADE®, Centocor), adalimuab (HUMIRA®, Abbott
  • the IL-1 antagonist may also be combined with HMG-CoA reductase inhibitors, such as LESCOLTM (Novartis), LIPITORTM (Pfizer), MEVACORTM (Merck), PRAVACHOLTM (Bristol Myers Squibb), ZOCORTM (Merck) or anti-lipidemic agents such as, COLESTI DTM (Pfizer), WELCHOLTM (Sankyo), ATROMID-STM (Wyeth), LOPIDTM (Pfizer), TROCORTM (Abbott), PPAR ⁇ agonists, thiazolidinediones such as PPAR ⁇ and/or PPAR ⁇ agonists, and mixtures thereof.
  • HMG-CoA reductase inhibitors such as LESCOLTM (Novartis), LIPITORTM (Pfizer), MEVACORTM (Merck), PRAVACHOLTM (Bristol Myers Squibb), ZOCORTM (Merck) or anti-lipidemic agents such as
  • compositions comprise a therapeutically effective amount of an active agent, and a pharmaceutically acceptable carrier.
  • 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.
  • 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.
  • the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings.
  • the composition may also include a solubilizing agent and a local anesthetic such as lidocaine to ease pain at the site of the injection.
  • a solubilizing agent such as lidocaine to ease pain at the site of the injection.
  • the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • 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 invention provides methods of treatment comprising administering to a subject a therapeutically effective amount of an IL-1 antagonist.
  • the agent is substantially purified (e.g., substantially free from substances that limit its effect or produce [0049]
  • 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, 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.
  • Administration can be acute or chronic (e.g. daily, weekly, monthly, etc.) or in combination with other agents.
  • the active agent can be delivered in a vesicle, in particular a liposome (see Langer (1990) Science 249:1527-1533).
  • the active agent can be delivered in a controlled release system.
  • a pump may be used (see Langer (1990) supra).
  • polymeric materials can be used (see Howard et al. (1989) J. Neurosurg. 71 :105).
  • 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. Patent No.
  • a nucleic acid can be introduced intracellular ⁇ and incorporated within host cell DNA for expression, by homologous recombination.
  • IL-1 trap the IL-1 antagonist of SEQ ID NO:2
  • RA rheumatoid arthritis
  • CRP levels were measured at weeks 2, 3, 4, 6, 8, 10, and 12.
  • the C-reactive protein assay was performed by immunonephelometry (Dade Behring nephelometer). Polystyrene particles coated with monoclonal antibodies to CRP were agglutinated when mixed with samples containing CRP.
  • the intensity of the scattered light in the nephelometer depends on the CRP content of the sample and the CRP concentrations are determined versus dilutions of a standard of a known concentration.
  • Eligible patients were males or females between 18 and 75 years of age (inclusive) who had a diagnosis of RA, with disease duration of no less than 6 months. Patients had to have at least 10 swollen and 10 tender joints (58/60 joint count) upon entry into the study at screening and at baseline, a CRP ⁇ 0.3 mg/dL, and had incomplete responses to conventional DMARD therapy.
  • IL-1 trap (SEQ ID NO:2) was provided in sealed, sterile, single-use 3-mL vials containing 1.2 mL of IL-1 trap at a concentration of 12.5, 25, or 50 mg/mL in a solution of 150 mM sodium chloride, 0.2% polysorbate 20, 5 mM sodium citrate, 5 mM sodium phosphate, and 20% sucrose, at a pH of 6.
  • IL-1 trap was administered as a 1.0-mL subcutaneous (SC) injection alternating among the deltoid area, abdomen, and anterior thighs.
  • SC subcutaneous
  • Placebo consisted of vehicle solution (150 mM sodium chloride, 0.2% polysorbate 20, 5 mM sodium citrate, 5 mM sodium phosphate, and 20% sucrose, at a pH of 6) provided in identical vials and administered as a 1.0-mL SC injection alternating among the deltoid area, abdomen, and anterior thighs. Each patient was to receive 12 SC doses of study drug or placebo over 12 weeks. [0055] Results. Mean change in CRP (mg/dL) was 0.072 for the placebo group, -0.675 for the 25 mg group, -1.021 for the 50 mg group, and -1.363 for the 100 mg group.
  • Fig. 1 is a graph of the median percentage change from baseline serum CRP values over time.
  • Example 2 Effect of Two Formulations of IL-1 Trap on Serum CRP levels in Volunteers
  • Study design A study was conducted to determine the effect on serum CRP of two formulations of IL-1 trap injected in a range of volumes subcutaneously to normal volunteers.
  • ⁇ n medication use except as-needed analgesics (at protocol specified times) and/or oral contraceptive pills.
  • IL-1 trap formulations and placebo. All test materials were injected sub-cutaneously or intravenously.
  • the IL-1 trap (SEQ ID NO:2) was administered as single dose subcutaneously of 50 mg, 80 mg, 104 mg, 120 mg, 160 mg, 240 mg, 320 mg of the IL-1 trap. 300, 500, 1000, and 2000 mg was administered as an intravenous dose. Placebo was administered as either a subcutaneous or intravenous dose.
  • Example 3 Effect of IL-1 Trap on Serum CRP on Adults with Autoinflammatory Disease
  • IL-1 trap was administered as a 3 100 mg subcutaneous doses given in 3 consecutive days (days 1-3) to subjects with clinically active autoinflammatory disorders, including the CIAS1- associated disorders, FMF, and adult-onset Still's disease.
  • CRP (mg/dL) was measured as described above on one or more of days 0-29 after administration of the trap.
  • Baseline values for CRP and CRP levels four days after the last 100 mg dose are shown in Table 2. Significant decreases in CRP levels were achieved within four days of administration.

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Abstract

Procédé de réduction d'une protéine C-réactive (CRP) chez un sujet, consistant à administrer au sujet une quantité thérapeutique d'un antagoniste de l'interleukine 1 (IL-1), CRP étant réduite. L'antagoniste IL-1 est, préférablement, une protéine de fusion de liaison IL-1 (piège IL-1), comprenant préférablement SEQ ID N°2.
PCT/US2006/003866 2005-02-02 2006-02-02 Procedes d'utilisation d'antagonistes il-1 afin de reduire la proteine c-reactive WO2006084145A2 (fr)

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
WO2008051496A3 (fr) * 2006-10-20 2008-10-30 Regeneron Pharma Utilisation d'antagonistes il-1 pour traiter la goutte ou la pseudo-goutte
US7632490B2 (en) 2006-10-20 2009-12-15 Regeneron Pharmaceuticals, Inc. Use of IL-1 antagonists to treat gout
JP2015120704A (ja) * 2009-05-29 2015-07-02 ゾーマ （ユーエス） リミテッド ライアビリティ カンパニー ＩＬ−１β抗体およびその結合断片の心血管関連の使用

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WO1993024134A1 (fr) * 1992-05-22 1993-12-09 Genta Incorporated Traitement de l'hyperproliferation cellulaire par inhibition de l'interleukine-1
EP0879889A2 (fr) * 1997-05-19 1998-11-25 Smithkline Beecham Corporation Un membre de la famille de l'interleukine-1,iL-1 delta
WO2004022718A2 (fr) * 2002-09-06 2004-03-18 Amgen, Inc. Anticorps monoclonal therapeutique anti-il-1r1 humain
WO2004100987A2 (fr) * 2003-05-06 2004-11-25 Regeneron Pharmaceuticals, Inc. Procede d'utilisation d'antagonistes de l'il1 pour le traitement d'hyperplasie neointimale

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WO1993024134A1 (fr) * 1992-05-22 1993-12-09 Genta Incorporated Traitement de l'hyperproliferation cellulaire par inhibition de l'interleukine-1
EP0879889A2 (fr) * 1997-05-19 1998-11-25 Smithkline Beecham Corporation Un membre de la famille de l'interleukine-1,iL-1 delta
WO2004022718A2 (fr) * 2002-09-06 2004-03-18 Amgen, Inc. Anticorps monoclonal therapeutique anti-il-1r1 humain
WO2004100987A2 (fr) * 2003-05-06 2004-11-25 Regeneron Pharmaceuticals, Inc. Procede d'utilisation d'antagonistes de l'il1 pour le traitement d'hyperplasie neointimale

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008051496A3 (fr) * 2006-10-20 2008-10-30 Regeneron Pharma Utilisation d'antagonistes il-1 pour traiter la goutte ou la pseudo-goutte
US7632490B2 (en) 2006-10-20 2009-12-15 Regeneron Pharmaceuticals, Inc. Use of IL-1 antagonists to treat gout
JP2010506936A (ja) * 2006-10-20 2010-03-04 リジェネロン・ファーマシューティカルズ・インコーポレイテッド 痛風および偽痛風を治療するための、ｉｌ−１アンタゴニストの使用
US7820154B2 (en) 2006-10-20 2010-10-26 Regeneron Pharmaceuticals, Inc. Use of IL-1 antagonists to treat gout
US8114394B2 (en) 2006-10-20 2012-02-14 Regeneron Pharmaceuticals, Inc. Use of IL-1 antagonists to treat gout
AU2007309470B2 (en) * 2006-10-20 2013-05-23 Regeneron Pharmaceuticals, Inc. Use of IL-1 antagonists to treat gout and pseudogout
JP2015120704A (ja) * 2009-05-29 2015-07-02 ゾーマ （ユーエス） リミテッド ライアビリティ カンパニー ＩＬ−１β抗体およびその結合断片の心血管関連の使用
US10611832B2 (en) 2009-05-29 2020-04-07 Xoma (Us) Llc Cardiovascular related uses of IL-1β antibodies and binding fragments thereof

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