AU2011224099A1 - Methods of using IL-1 antagonists to treat autoinflammatory disease - Google Patents

Abstract

Case No. AU 2011224099 Interleukin-1 (IL-1) antagonist fusion proteins useful in the treatment of autoinflammatory diseases, such as familial Mediterranean fever (FMF), Neonatal Onset Multisystem Inflammatory Disorder NOMID/CINCA, Muckle-Wells Syndrome (MWS), Familial Cold Autoinflammatory syndrome (FCAS), and tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS).

Description

AUSTRALIA Patents Act COMPLETE SPECIFICATION (ORIGINAL) Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art: Name of Applicant: Regeneron Pharmace-uticals, Inc. Attual Inventor(s): George D Yancopoulos, Scott Mellis, Margaret Karow, Joanne Papadopoulos Address for Service and Correspondence: PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Meibourne 3000 AUSTRALIA Invention Tille METHODS OF: USING IL-1 ANTAGONIStS TO TREAT AUTOINFLAMMATORY DISEASE Our Ref . 925281 POF Code: 134671/134671 The following statement is a full description of this invention, including the best method of performing it krlown to Applicant(s: METHODS OF USING IL ANTAGONISTS TO TREAT AUTOINFLAMMATORY DISEASE The present application is a divisional application from Australian patent application number 2005249570, the entire disclosure of which is incorporated herein by reference. SAC 'GRC2IJND Meld of the Invention [0001] The Irivnhtion relates tO rnothods of usibg interleukin-i (IL-'i).sntgdniatc to treat autolrfiammatory diseases, such as, for example, Including familial mediterranean fever (FMF), NOMID)CINCA, Mtwkieaiells Syndrome, FOAS, and tumour necrosis factor receptor-aselodated periodic fever syndivmo (TRAPS). Description of Related Art [0002] One important group of autoinflammatory disorders encompasses autoscmi dominant conditions aucolaled with muLations in CIA3-1, a gene that enccdos a pyrli-related protein called "cryopyrhi" (Feldmann at al. (20(2) Am. J. Hum. Genet. 71198-203; Hortmen at el. (2001) Not. Genet. 29:301-305). These disorder; InClde Neonatal Onset Mulisysttm Inflammaiory Disorder (NQMIDIiNCA), Muckle.-Wells Syndrome (MVS), end Familial Cold Autolnfiammatory Syndrome (FCAS). These disorder present a spectrum of clinical manifestations ranging from FGAS beIng the mildest to the seriously disabling disease of NOMID/CINCA. An urfioarrasJ[ke skin rash is common to the entim epoch urn of these diseases. In patents wlth FCAS, this rash ts induloble by cold exposure while mosi natlants with MWS or NOMI D present with daily rashes that are consistently provoked by a number of dIfferent stimuli, Conjunctivitis is presenting all forms of disease expression, however, hearing loss, aseptic meningitis and ;rthritla are mainly seen In patlerts wilt MWS and NOMID/ CINCA. The disfiguring arid disabling body overgrowth at the epiphyses and patbllae Is.only seen in patents with NOMID/CiNCA. [0003] FMP its-sacessively inherited condition characterized by episodes of fever and serosidts or synovfts; some subjects also develop systemic amyloidvais (Balow et al. (1997) Genorris 44:280-291). The FMF gene encodos a novel protein called pyrin that Is the prototype of a family of molecIes 4nvpived In the regulatipn ol epoptosis (cell-death) and inflammation. The precise bicicherical methanism by which these proteins function.and bywhluh-mutatiorls cause disease Is still Unknown. [00041 Stills Disease (systemic onset juvenile idiopathic arthritis), Is manifest by spikIng levers, evanescent salmon color rash, arhdts, arthralgia, and hapatosplenomegaly (Masson et al (1995) Rev. Rhum. Engl. Ed. 32746-757; Slageal t al, (2000.) Arthritis Rheum. 43:2402-2409). There are as yet no definitive genetic assocIations wlth Still's Dicoaso and the pathogcnesis Is poorly understood. Interestingly, many of the signs and symptoms of SIll s disease nit siilailn those with autrinflaun.iwkry dismm, Stil.s Disease typically first bcpur .duringchld.ocod, but can also h eve its onset in adulthood. 1A.

[005 S-InitAV, KOWaso ki 4 isiase is: a dlsea,, attaetlngr ibhld en that.i co r~ by foivsr.,, mswnlilng -nn wl PMhr amc~n,~ t. rkM.;h. ai~i~wORas Vortti IiiTflaiMM-Ai Mat~ can etiusb diseases are Blau's syndrome uind Early Onset Sarcoidosis (EOS), both o1 which are caused by a gain of function mutations- in NOD2, a protein similar to Pyrin, and cause rash. grariulomatos s, arthitis ahd uveilis. Other diseases thaf have alsd been considered auto41flammatory include, Hidradenitis suppuraflv, Behcet's, 5 hyperimmuncglobulinemia D with periodic fever syndrome (HIDS), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), and Pyogenlc sterile arthritis, pyoderma gangrerosurm and acne (PAPA syndrome), [0006] The pathogenesis of auteinflammatory disease is rot completely understood. There is a growing body of evidence that interleukin-1 (IL-1) plays a role in a number [0 of these conditions and that tsrgethng of this cytokine can provide Important benefits (Hoffman et al. (2004) Arthriti. Rheum. 50:35-349). There is clearly a need to develop improved therapeutic treatment of these autoinfla-mmatory diseSa.s, [0006a] The discussion of documents, acts, materials, devices, aricles and the like is included in this specificatior solely fwr the purpose of providing a context tor the 5 present invenltionl. it is not suggested or represented that any or all of these mntters formed part of the prior art base or were common genera knowledge in the Field relevant to the present ;nventiQn as it existed before the priority date of each clai of this application. [D006b] Throughout the description and claims of the speciication. the word 20 "comprise" and variations of the word, such 9 tomprising" and 'momphiaa, is not intended to exclude other additives, componerits, intagers or steps. BRIEF SUMMARY OF THE INVENTION [0007] In a first aspect. the invention features a method of treating, inhibiting, or 2 ameliorating an autoirflammatory disorder, comprising administering to a sujbjct ih need an nterleukin 1 (IL-1) aritagortist An IL-1 antagonist is a compound capable of blocking or Inhibiting the biological action of-L-1, including IL-1 -binding fusion proteins. In a preferred embodiment, the IL-1 antagonist is an IL-1-specfic fusion protein comprising two IL-1 receptor components and a mutimerizing component, for 30 example, an t-I fusion protein trap antagonist (an "IL-1 trap") described in U.S. patent publication No. 2003/0143697, published 31 July 2003, in 8 specific ernbodiment, the IL--1 antagonist is the fusion protein shown in SEQ ID NO; 4, 6, 6, i0, 12, 14, 16, 1.8, 20, 22, 24,.26. A preferred fusion protein is shown in SEQ ID NO:10, The invention encompasses the use of an IL-i-binding fusion protein 35 substantially identical to the protein of SEQ ID NO, 4, 6, , 10, 12. 14, 15, 18, 20: 22, 24, 26. that is, a prielin having at least 95% identity, at least 7% identity, at least 95% identity to tho protein of SEQ ID NO; 4, 6. 8, 10, 12, 14, 16, 18, 20, 22, 24, 26 2 arid capable of bniding and inhibiting IL-1. Further, in specific embodiments, the IL-1 antagonist is a fusion proteinecomprising one or moro imrmunoglobutlin-derived components in place of orie or more receptor components. In specific embodiments, the IL-1 antagonist comprises one or more imrunoglobulin-derved components 5 specific for IL-1 arid/or an IL-1 receptor. [0007a In a further aspect, the invention features an interleukin 1 (IL-1) fusion protein antagonist comprising two iL-1 receptor components and a multimerizing component for use in a method of treating, Inhibiting, or ameliorating an autoinflammalory disorder, disease, or condition, wherein the IL-1 fusion protein antagonist is 1 0 administered weekly. [000.8 The subjett being treated is mist preferaby a human diagnosed as suffering frorn an autoinflarnmetory disorder. More specifically, the subject is a human adplt -r ch 1d diagnosed with an autoinfiammatory disorder associated with mutations in CIAS 1, such as Neonatal Onset Multisysterri Inflammatory Disorder (NOMID/CINCA), 15 Muckle-Wells Syndrome (MWS), Familial Cold .Autoinflamrnmatory Syndrome (FCAS); farnilili mediterranean fever (FrMF); -systemic onsot juvenile idiopaithic arthritis (Stirs Disease), tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS), or Kawasaki Disease, [00091 Tne method of the invention includes adminislmtion of the IL-1 antagonist by 20 any means kryown to theurt, for example, subcutonoouG, intramuscular, intonacolo, intrvenous, iransdermal administration or oral routes of administration. Preferably, administration is subcutarneous or WO 2'01179J5 PCT/TS2005)1 674 inttgyn& [0019] In a second aspect, the invention features a method-of treating, inhibiting, or amellorating a di-seasaor condilon selected front the group consistIng of NOMID/CINCA, MWS. FGAS, FMP, StIlls iseaso, TRAPS, and KawasakI DIsease, the method comprising adminlstering to a subject in need an irgerieukin -I (IL-1 antagonist. in a pr.cfonvi on~bodimnent,. the IL-i ontagonlist is a fulon protein capable of trapping 11--1. In a specrifi embodiment the IL-1 antagonist Is the fuslon protein shown in SEQ ID NO: 4, 6, 8:, 'It, 12,14, 16, 1, 20, 22, 24, 26, or a substantially Identical proteIn capable of binding and inhbilting IL-1. A pieferred IL1 antagonist is shown in SEQ ID NO:11 Praferasbly, the subJect treated Isa dhlid or adult human diagnosed with the dlsesse:or condmokn. [0011] In a third spedt, te Invobtion features a method of treating, Inhfbitlng, or amnelrorating Neonatal Onset Mulisyastem infamnatory Disorder (NOMID/CINCA), comprising administasrng-to a subjct In rsad an infterleuklr I (IL-1) antagonst In a p-eferrtd rnbodimant, the IL-1nagonist I a fusion protein capable aftrappinU !L-,. lit a-speerte embodiment, the iL-i antagonist is the fusion protein scwn in SFQ ID NO: 4, 8. 10, 12,14, 16, 18, 20.22, 24 26, or asubstaritilly icendial protti capable of binding and Inhibiting JL-1. A pmferred iL-1 antagonist is shown In SEC ID N0:10. [00121 In a fourth aspect, the Invention features-a method of treating, inhibiting, oramelorating Muckle-Wells SyndIonie (MWS), the method compdsIng adminLterlng to a subject in need an Interleukin I (IL-1) anegorIst. In a preferred embodiment, the IL- an1 tagonistis a vision protein capable of trapping IL-1. In a specidc embodiment, the IL-1 ardaonist Is tho fulon protein show in SEC ID NO; 4, G, 8, 10, 12,14, 13, 1, 20, 22, 24, 26, or asubstantialy ide.nticaI prt&in capable of Unding and Inhibiting IL-1. A preferred IL-1 antagonist is shown in SEQ 10 NO:10: [0013] I.n a fifth aspeot' th invnrin fokaturc a isthod of treatIng, inhibiting, or amellorating Familial Cold AuLninlammar y Syndrome (FCAS) the method comprlsing admninlsering to a oubjectin need an inturiouki'n I (IL.-) antagonist. In a preferred embodiment, the 1.-I antagrrst Is a fusion protein capable of rapping IL-1. lit a specific embodiment, the IL-1. antiagonat is the fusion protein shown In SEQ ID NO: 4 6, 8, 10, 12,14, 16, 16, 20, 22, 24, 20, or a substantially idontlcal protein capable of bInding and InhIbiting ILA. A preferred IL-1 ontagqonlt I shown In SIQ ID Nc:10. [0014] In a sixth aspect, te Invention features a method of treating, InhibIng, or amellIrating frrmll medi-enanearn fever (FMF), the melion comprising administering to a subject in need an Interleukin 1 (iL-1) antagonist. In a preferred embodiment, the IL-1 antagonist is a fusion proteIn capable of trapping IL-3. In a spectifc erntodiment, the IL-1 trap is the fusln protein shown in SEQ 10 NO:4, 6, 8, 10, 1214, 16, B. 20, 22, 24, 28, or a substantially idontloni protein capable of binding and inhibiting IL-1. A proforrod 'L-1 trap li shown In SEQ ID No:10. [fn05In ]n- a seventh aspect, th-e Invention features a method of treating, lIhlbltlng, or amelioraang systomi onset juvenile llpathic arthriti.(Stls Diseasa.), the method compising adniniaterIng to a subject in need an interleukin 1 (IL-1) antagonist. in a preferred embodiment, the IL-1 antagofnst Ka uori pretan dapable or.frapptog JL-1. in a specific embodIment, thb 1L-1 3 WO 20051117945 PCT/USS/01%74 :n SEQ ID NO: 4, 6,8,10, 1,14, 16, 1t, 20. 22, 24, 20, or a substantially identical protein rapable of binding and 1rihlblitig IL-1. A preferred 8L-1 Lrap .s shown in SEQ ID NO:10. [00:161 In an eighth aspect, thi6 Ir/6Mloh feaures a method of ftetlit, Ihibitinor Anelloatih tumour necrosis factor -ceptor-sloclatud rtdicr foyer syndrome (TRAPS), tha mulhod comprising adrminIstedng t a subject in need an IL-1 anigourist. In a poferred nbodiment, the IL-1 antagonist is a fusion protein capable of trapping IL-1. In a specific embodirneant, the IL1 anteawnistls fhe fuslon protein shown in SE ID NO: 4, 6. 8,10, 12,14,16. 1, 20, 22, 24, 2e, or a substantially Identical protein capable of binding and fnhibting |1 1. A pfererd IL-1 mp is shown in SEQ ID NG:1 II [0017] In specificermbodirrnsiof the therapeutic method of the Invention. the subject is treated with a combination of a first IL-i-binding fusion protein trap molecule and a second therapeutic agent. The second therapeufle agent may be a sepond IL-1 antagonist, such as, for example, s second IL-1 -binding filmon protein trap, nakinir (Klneret®, Amgen), a recombinant, nonglvcosyipted form of the human IL-1 receptorantegonlst (IL1 Ra), or an anti-IL-T drug such as IL-18EP or a derivatva, -an IL-18-binding fusion protein trap (an "IL-18 trap"). and-iL-18, unti-IL 18RI, or anti-IL-18Raop antibodies cr antibody tragnints, Other co- therapies include low dossD colchino for FMF, aspirin or other NSA.Da, -steroids such as prednisolone, methotroxato, low doss cyclosponno A, TNF inhibitars sUieh as Ehbrel@, or HumIHral,, otler inflanitory Iniictors ach as inhibitors of cOpae-1, p38, IKK1/2, CTLA-4Ig, anti-IL-6 or anti-ILGRa, etc. [00181 in a ninth aspect, the irvonlwr fwetures n thnmpeuiJtei method of treating an autolnrnmatoy disease or condition, omprising adrninistering a pharmaouficl conooiitlin mmpdsiing aUn IL-1-bInding fasion protein trap and a pharmiceutioaly acoplable carrier. in cie ernbodIment., the IL.-1-bindng fusion protein trap is administered in a dose ronge of 1-20 mg/kg on a weekly basis for a treatment period of between 1 wueek to on year or noru. In brother ernbedlment, a total iL.-1-bIndng fumlon protein isadmniterad ir th range if 50-2000 rg. which may be provided ir a single dose or In sequential doses over a perid of lime such as a period of weeks or rmonlths, [0019] Other objects and advantages will become apparont from a review of ti ensrang detailed rJesripiiari DETAILED DESCRIPTION [00201 Before the present rielhiads are described, it I.ta be understood that.thIs invention ik.not IlmItod to particular methods, and oxporimefntal conditions described, as such methods and conditiorns msy voy. htis aiso to be understood fhat the .temnindlogy used herein is for the purppieo of describipg parlioular embodiments only, and is not intended to be limiting, since the scope of the present Invention wiH be limited only lo he appended lalms. [0021] As used In this specIfIcation and the apprided claims, the singular foms "a", "an", and th" include plural references uniess the context clearly dictaies.ntherwim. Thus for example, a reference to "a method" includes one or more mretiods. arid/or steps of the type described 4 WO 203tJ5/ *7tIIv. PC/u S2ooLsu I~67,; hP drent to those persons skillMd in the art upon reading thIs disclosure and so folth. [0022] Unlles deliried othetwisae, al technical and scintltif teims used hollh have the same moaning as commonly undereltod by one of cdlInary skill In the art to which this Inventlon belongs. Although any methods and materials sirmar or eqivaant -to those described herein can be usod In the practice or testing of the present invention, the preferred method. and materials are now described, General Description [0023] MuitotionsO in tie gonO CP1S1 are now recognIzed as being responsible for threo rare genetic syndromes: Neonatal Onset Multsystem Inflammatory Disorder (NOMID), Muckle-Wells Syndrome (MWS), and Farrilai Cold AutoInflammatory Syndroma (FCAS) (Hoffman ot al. 2001 Naure 20:301-305; Feldmainn et al, 2002 Am J Hurn Genot 71:198-203; AksentJevloh ot-al. 2002 Arthritis fRhsum:40:3340-3348). In aqgrgatci, these conditions are known as "CAPS", an acronym for "CMS1 Associated Perloclc Syndrornes" CAPS disorders are exceedIngly rare; with apprnximately 200-300 adults and children in the U.S. With FCAS and significantly fewer adults with NOMID or MWS known to have these conditIons; The rarity of these cendltlons, particularly NOMrD and MWS, arbprobably due to effects of diioassa 6voity on suhiival or reproductive fitness. [0024] CAPS are inherited In an autosomal dominant manner, with a.sporadic r farnilial pattrn. CIA:S1 erPodes a prcttn called NALP3 that is a component 4f the "ir-tiammasome", a subeellular enzyme cornplex that regulates the activity of caspase 1. Caspase I i's the enzyme that cleaves the Inactive pro-form of the proinflammaiory cytokjne, IL-1, Into its bilogically active forrn (Agosdinl et a. 2004 supra). Mutations In CIA3S lead to. increased production af R-1 and numerous pathological oonsequees (Aksentjevloh et al 2002 supre), IL-1 strongly Indueos he production of acute phase reectanls in the iver, sch as C-reactive protein (CRP) and serum amylold A (SAA). [0025] The genetics of CAPS ate interesting in that there can be a number of different point mutations In CiAS1 associated with these syndromes (Sarrauste de Menthlere et a. 2003 Nucleic Acids Re5 3-1:202-2B5; Aksenijevich et al. 2002 supra). Some of those mutatkns are aseoolated with only one syndrome; others two. For example, sumS muliWlnR marny he sswmockted with FOAS as well as MWS; other mutations may be associatedwith MV/S and NOMID, ApproxImately 50% of patients with NOMfD co not have a recognized rnulsfin in-the coding region of C/AS1 In these patients, the diseasemay be due to an as-yet-unrerognized mulation in a regulatoty region or protein of CIAS1, or in another gene encoding a closely-related protUn in this pathway. FCAS f more genetically homogeneous than NOMID; almost al; patients with FCAS ahnrs a common mutation (Sarrrusto de Meathire et al. 2003 supra; Hoffman ot al, 2001 supra). [0026] CAPS disorders share common olinlcal features and present as a spectrum of Ilinical severity. NOMID Is the most seriously disabling, MW soemewiat less so and FCAS:is the east severe. CAPS disorders have overlapping features and here are indIviduals and kindred with WO 200NI 17915 ICTU S2005/i1674 uni X:($I riin 'ynl iptoms. Fealurte common to all these condtlon!; Includo fevers, uricaria-lke rash. arthritis or ailthralgia, mysgle, nirlalse, end conjuncivitis. However, the napctrum of symptorme [or any patient with a CAPS disorder may differ from that of another patient with the same disorder. A universal feature of native CAPS disese is laboratory-test elevation of acute phase reactants, such as CRF, SAA, Mnd/or Crythrocyte sedlritatIon rate (ESR): [0027] In NOMID. chronic aseptlc moningitis may lead to mental retardatlon and tllese patients may also suffer diafiguring and disabling bony overgrowth at the epiphyses and patells. Thesr patients rnay also suffer blindnres due to-optic nerve atrophy that resuIts from Increased Intracranial pressure. MWS and NOMID 4r-, commonly associated with severe infammation that may innlude-the auditory system, meninoes. and joints, These pallents may suffer dally high spiking fevers and a chronic rash that frequently canges In distrilbuiiian and intensity. Patkeits may suffer hearing loss or deafnes. GonjurctMtis and papilledemr-a are frequently observed. Arrildotois.may ddvetop and lead to renal fallur due to chronic Inflammation and overproduction of acute phasa reactants (particularly SAA). MWS is also known as 'arnylodssis.-deafness. y ridrcdmlt [0028] The clinical signs and symptornD of FGAS are Induced by exposure to modesfly cold air (e.g. seasonal ferhiettire changes, ar 61nditlonlng). Patents may have froquant (sometimes daItly) episodes Ot a painful or prurlilo rash, favor, fatigue, malaise, headache, nausea and tNirst during cold months or in kkalions whete air dondltlonlng 13 proVaient In rnany locmlce, this may lytude- MOt w iod places. FOAS is a source of frequent pain to patients and may restrict their Employment, socla, and recreational oppoiiriities. Up tb 2% 6f pts with-FCAS develop. aryiiduels; a !fe-throatonlng condition. T his frequency is substantially higher than the rate- of smyloidosis in ine-general community. The genelis and natural history of FCAS are described in detail Hcffrm~ani et al. 2001 Nature 29301-30& and Hoffrnan- et ,L 2001 J:Allergy cin Immurol 108:615-620. [0029] By the term 'blocker", "InhIltor, or "antagonist is meanta substance lit retards or prevents a chemical or physiological reaction or response. Common blockers or Ihtbitors include but ar not Irlilled to antisense rnoleculos, ansbodles; antagonIsts and their derivatives. More specilcally, an example of an IL-1 blocker or iibhlitor is an IL-1 antagoniAt.includiig, but not limited to, an IL-1 fusion protein trap antagonist, whlch binds and inhlblts IL-1. [0030] By the term "thorapoutically effective dose" lo meant a dose that produces the desired effect for which it is administered. The exact dose wil depend on the purpose of the treatment, -and wllI be ascertainable by- one skilled in the art using known techniques (see, for example, Lloyd (1999) The Art, Stience and Technology of Pharmaceutical Com pounding). [0031 13y the term 'substan ially Identical" is meant a protein sequence having at least 95% Identity to an orninro acid sequence sciocted from the group consisting of tire amino acid sequences SEQ |D NOs:4, 6, 8, 10 12, 14, 16, 1: 2G, 22, 24, and 26, and capable of binding IL 6 WO 2[)Ij5A117945 PCTU82)5/019674 1 IL n lIO Mbk 6IN9 F51 'itU IL-1. [00321 The term Identit" or 'homology" le construed to mean the psrcentagn of amine acid residues in the candidate sequence that are idendial With the residue of a corresponding serqlence in wh'ch It is compare, nfter aligning the equences and introducing gaps, if necessary to achIevo tho maximum porcont Lentfty for the entire sequonce, and not considering any conservative substitutions as part of the sequence identity. Neither N- or G-terminal extenslons nor inserdons wll be construed as reducing identity or homology. Methods and ompUtar programs for the alignment are well known In the art. Sequence Identity may be measured uslni ooquonco.onLjki& saftwaro (6g. Soqience Analysis Softwar PAckrge, Genetics Computer Group, University of Wisconsin BgFechnology Center, 1710 Urlverslty Ave., Madison, Wis. 53706). This software matches sinilar.sequincei by assigning degrees of homology to various substtutions, deetions, and other modificatlon. IL-1-Binding Fusion Protein 'trap Antagonists [Ol33] Interlaukir-1 (L1) traps are multimes offusion protens containing IL-1 receptor componens arid a rultimorlzing component capable of intermoting with !he mulimerizing component present In another fusion protein to form a higher oider 4nructure, such as a dimor. The IL-1-bIndng fusIon proteins usefu In the methods of-the Invention Include two disInct receptor components that hind a single cytokiie, resutinfr in the generation of antagonists with drantipaily Inmemssed afflnity:over thA offered by single ompoosn rtagents, The IL-1-binding fulon protein traps are comprised of the extracellular domain of human -1- R Type I (IL-1RI) or Typo i (IL-1 RIi followed by the extraelluiar domain of human iL-1 Accessory protein (IL-1AcP), followed by a multimerizing comrponent, in a preferred embodimrent, che muflrmeriZing comporient is n irnrhunoglobuln-deriyd domain, such as, for example. the Fe region of humni ig, including part of the hinge region, the CH2 and CH3 domains; An immunoolobufln-derived domaIn may be sedected from any of the majordcaases of imnrunoglobuilis, including IgA. Ig D, lgE, IgG and 1gM, end any subclass or Isotype, e.g. igGI, igG2, gG3 and IgG4: IgA-1 and lgA-2, Alterrively,, the iL--bnding.fusln proteins useful In the method of the invention are comprised of the extracell~iar domain of human b-LIAP, followed bythe extranellular domain of human IL-1RI or 1-1R FtI, followed by a rnuoimrlzirg component. For a more detailed descriptIon of the IL-1,hinding fusion protein traps, sea WO 001h8932, Preferred IL-I antagonists have the amino acid sequenrca shown in SE-Q ID NOs: 2, 4, 6 8,. 10, 12,.14, 16, 18, 20, 22, 24, Ond 26, or a sLIstantally idontlcsi protOIn toast 9l/o identity to a sequence of SEQ ID NO: 4, 6, 8, 10, 12; 14, 10, 18, 20, 22, 24, or 26, and capable of binding and inhlbiting iL1. Treatment Population (0034] The-therapeutic methods of the invention are useful for treatlrg indlviduals affected with CIAS-4 mutation disorders (NOMID, MWS, FCAS), FMF, TRAPS, or Still's DIsOase. Commonly accepted dlajnostio iitei for C/AS-4 mutatIon associAted disoas (NOMIO, MWS, FCAS), Familial Mediterranean Fetter, or Still's Disease (adult- orju~isniie- orset) are know to. those skilIed and capable of bindihy and inhibiting IL. Further, in specific embodiments, the IL-1 antagonist is a fusion protein comprising one or more imrnunpglobulin-deried components in place of ore or more receptor components, In specific embodiments, the IL-i antagonist comprises one or more immunoglobulin-derived components specific for IL-1 and/br an IL-1 5 reuepator. [0007a] In a further aspect; the invention features art interleukin 1 (1L-1) fusion protein antagonist comprising two IL,1 receptor cormponents and -a multimerizing component for use inwhen- Lsed for B method of treating, inhibiting, or ameliorating an autoinflammatory disorder, disease, cr .ondition Neonatal Onset Multisystem Inflammatory Disorder (NOMID/CiNCA), 1:0 Muckle-Weds Syndrome {MWS), Farmilial Cold Autoinflamrnmatory syndrome (FCAS), familal Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS), or systemic onset juvenile Idlopathic.arthritis (Still's Disease.); and/or an autoinflarnmatcry disorder, disease, or 6ndition that is associate Wlth a ruttion In CIA S-I, wherein the IL-1 fusion protein antagonist is administered weekiyin a dose range of 1-20 15 mg/kg on a weekly basis. [0008] The subject being treated is most preferably a human diagnosed as suffering frorn an autoinflarnratory disorder. More specifically, the subject is a human adult- or child diagnosed with an autoinflammatojy disorder associated with mulations in GIAS-1, such as Neonatal Onset Muldsystem Inflammatory Disorder (NOMID/CINCA), Muckle-Wells Syndrome (MW S), 20 FlMilil Cold Autoiflamnatory Syndrome (FCAS); familipi mediterranean fever (FMF), systemic onset juvenile idiopathic arthritis (Stil's Disease), tumour necrosis factor receptor associatec perodic fever syndrome (TRAPS). or Kawasaki Disease, [0009] The method of the invention includes adtihistratioh of kne I1-1 aritagrist by ,Eoy means. known to the art, for example, subtutaneous. intramuscular, intranasal, Intravenous. 25 transdermal administration or oral routes of administration, Preferably, administration is subcutaneous or 7a WO 2005/117945 PCTUf2H15J19674 in tf pIti .osed with FMF, the tihrapeutic method of the invention miiay be particularly usoful tar thoso with disease refractory to therapy with colohicine. Methods of Admriltratori [0035] The Invention provides methocis of treatment corirising adminititing to. a subject at effective amount of an agent of the invention. in a preferred aspecl, the agent Is substantially purified (vg., substantially freefrom substances that Iirriit.it. effect or produce undesired sid effectst: [0036J Various delivery systems are knom.and canbe used to administer an agent of the irvntiOn. e.g., encapsulion In lpcsOreg, microparticles, microcapsules. recombinant cells capable of expressing the compound, receptor-medlated endocytosis (see, e.g., Wu ond1Nu, 1987, J. Bt?. Choem. 262:4429-4432), construction of a nucleio acid as part of a retroviral or other vector, etc. Ivietliod of inluducion can be eliterel or parenteral and include but are not limited to intmdemnl, Intramuscular, Inlraperitoneal, iritravonoue, subcuteneous, Intranasal, epidurol, and oral routes. The compounds may-be administered. by any convenient route, for exrnple by Infusion or bolus injection, by absorption through epithelial or mrucocutaneoutliiings(ag, orsi rnucosa, rectal andinlesiinal iucoec, etc.) and may be administered together with other biologically active agents. AdmInIstration can be systenlo or local In addlion, it may be desirable to introduce the phatmaceutioei compositions of the Inven tion into the cenirs. nerouS system by any suitable route, includIng Intraverrfcular and Intrathevel Injection; intraventricular injection rnay be facilitated by an Intraventricular catheter, foi example. attached Lu a rrservoir, sudh as an Onimaya resemolr. Pulmonary administration can also be erployed, e.g., by use of an nhaler or nrbullier, and formulation with an aromsolizing agent. 0037] In a specific urhbadimont, it may be desirakla to administer the pharmaceutical compositions ot toe Invention loodlly to the area in need of treatment, this may be achieved, for example, and not by way of Rmitation, by local infusion during surgery, topical application, eg, by injection, by means of a cathater, or by means of an Implant, said Implant boing of a porous, non pomus, or gelatinous material. Including mon-ibranes, such as slalastic mombranes. fibers, commercial skin substitutes or angioplasty balloons or tents. [003S] In another eibadltsnt, the-actvd ayent can be delivr-ed in a vesiclo, in particular a liposone (sea Langer (1990) Science 249:152y-15i), In yet another embodiment, the -active agect can be delivered in a d.nVolied reledse6 9stem. iri 6ne eribodiment, a pump may be used (see Longer (1990) sJpra). In another embodiment, polymeric material's can be used (see Howard et al. (1989) J. Neurosurg. 71'105 ), In another ardbocliniat whsi-e theactivQ agonl of the InventIon is a nuclelo acd encoding a protein, the nuclei add can be administered In vVO to promote expression of its encdred protein, by coristructrig it as part of ad roprite hdcieib acid expnmIon veScIr and administering it so that it beromes Intranellulor, a.g, by une of a retrovial vector (see, for example, US. Patent No. 4,980,2&6), or by direct injenilon, or by use of microparticle borbardment (e,g., a gene gun; Biolistic, Dupontl or Goating With Iipds or cel surface reenptm.n or trandonkIng agents, or by administerlng It in inkage to ahomeobox-lik4 WO 205/117945 PCT/USO2O/019674 pa? 1r c (see S.g, JoHot et al., 1991, Proc. Neil. Acad. Sd. USA 88:1864-1868), etc. AItornatively, a nucleic acid can be Introduced Intracellularly and incorporated within hot cil DNA For expression, by-homalogous recmbilnation. Combination Therapies [0039] in numerLIS smbodrnents, the L-1 antagonista useful on the methods of the present invntion rey be adminstered in combination wlth one or mom additional compound or therapies. Combinatlon therapy may be simultaneous or sequential The IL-1-binding fusion protons of the inventon mby be combined with, tor axaripd, TNF-nhib[lUng sbgeits such as etanercept (Fnbrel@, Angen), intlIximac (Remicade@, Contocor). Humlrs@ (Abbott), thaildornld. steioids, adakihra-(KinartI@, Angnh) or dbchidihe. Gojchidine is a rhalihtay f therapyfor subjects with FMFl In tNs study, subjects wil not be removed from treatment with this redication. rr St1IIs la4nase (and classIcl autoiniaminatorj diseases), coInpounds subh as rrathctrexato, cyolosporina, chiorumbil cyclophosphamido (DMARD) have been used as monotherapy or in canbinstionwith no consistent response. Scme subjects respond to high. doses ofsterolds. DMARDs, and more recently anti-TNF agents have been used with variable success. The IL-i-bindrsg fusion pretelns of the Inverticn may also be combined with anti-IL-18 drugs. such as forexamniple, IL-18BP or a derivative, an IL--16-binding fusIon protein, anti-IL-18, aiti-1-.18N1 or ariLl-IL-1RacpL. Other co-therapies include low dose aolchins for FMF, aspirin or other NSAIDs, steroids suci as prednistone rethctexate, lo dpse cycIosporne A. TNF Inhibitors such as Enbrel, or Humira@, other inflammatory inhibitors such as inhibitors of Oaspase-1, p38, IKK1/2, CTLA-41g, anti-IL-6-ocr urti-ILGRa, etc. Pharmaceutical Comp9sitlore [00401 The present Invenlion ase provides pharmaceutica compositions. Such comiiposltions comprise a thorapouticliy -effective amount of an active agent and a pharmaceutioally acceptable carrier. The term "plarnaceutlcally acceptable" means approved by a regulatory agency of the Federal cr a state government or listed in the U.S. Pharmacupeia or other generally recognized pharnmacopela for use In animals, and more particularly, in humans. The term "carrier" rWfrs to a diluent, adjLvan, excipient, or vehIcle with which the therapeutic is admlinistered. Su9ch pharmaceutical carriers can be sterile liquids, such as water and cils, including those of petrolCum, nnimai, vegtebic or ynthelli origin, such as peanut oil, soybean oii, mineral oil, sesame ol and IMe like. Suitable pharrnneeuttiel-exciplents include starch, glucose, lactose. sucrose, gelatin, mait, rioe, flour, chalk, sllica ge, sodium steamato glycerl monistearate, tac, sedlum chloride, dried sidm mik, glycerol propylene, glycol: water. ethanol and the like. Thn composition, if desired, can also contaIn minor amounts of wetting or emulsifying agents, or pH buffering agents. These composition can take [he form of soludons, suspursions, emulsion, tablets, pills, ropsules, powders, sustained-release formulations and the ike. The composition can be forrniated as a supposihnry; with traditional binders and carrlera such as triglycerides. Oral fir'iulalon can include staridatrd carriers such s pharmaceutica grades of mannitol WO 2Ii5mi7t PCT/US2O15 7 4 fla re in66%odium. saccharine oelurose, arrgneslurn uarbonat., etc. Examples of suitable pharmaceutical car6ers are desernbed in "Remington's Pharmnoeutloal Scenes" by E.W. Martin. [00411 In a prfefrred embodiment, the composition I formulatkd In accordance with routine prOcedures as a pharmaceulical composition adapted tfr lntravnojs adminlstration to human beings. Where necessary, the composItion may also indAude a solubliz-ig agent and a local anesthetic such as liducairie to eese pan at the-sits of the injection. Where the composition is to bo administered by Infusion, It can be dIspersed with an infusion bottle contaking starlie pharmaceutical grade water or saline. Where the crompoailion 'a edmifatred by injcotior, an arnpouie of sterile water for injection or saline can be provided so that the Ingredients may he mixed prior fo administration. [00E421 The achive agents of the invendon can be formulated as neutral or sal forms. Pharmaceutcaily acceptable usits Include those formed with free amino groups such as those derived from hydrochloric, phosphoric, acetG, taxic, taetnlic acke, etc. and those formed with free carboxyl grouPs such as those derleed'frorm sodium, potassium, ammonlumn, calcium, terric hydrodes, Isopropylamino, triothylamine; 2-ethylamino ethanol. histidine, procaue, etc. [0043} The amount of the octiv agent of thn invention which wilI be effective In the treatment of delaydd-tyP hypersonahlIvitycan be determined by standard clinIcal techniques based on the present descdptlon. In addition, in vWtr assays may optIonally be employed to help identity optirnali dosage ranges. The prAese dses tP be emnoyed In the fornulation will also depend on tha route of administration, and the seriousnass if the cnditon.s and should be decided according to the Jdgnfr1t of the practitienor anrd oach ey bje's circumstances. However, siitable dosage ranges for Intravnous administration are generally up to about 2 grams of active compound. E'ffectIvo doses may be extrapolated from dose-response. curvesderlyed frOrmi k? vitro or-onimal model testeystemis. [00441 For systeilc admlnistradon. a therapeutically effective doso can be Getinattd InItiully from in vdro assays, For example, a dos can be formuiled In animal models to achieve a circulatIng concentration range that Includes the ICm as determIned In cell culture. Such information car be used to more accurately determine useful doses In humans. Initial dosages con also be estimated from in vri dats, o ly, animal models, using tochniqugs that are weil known in the art, One having ordinary skill in the art could readily opt!mize-administration to humans based on.animal data. [00461 Dosage anmiount and interval may be adjusted indMdualiy to provide plasma lovels of the compounds that ara sufficient to maintain therapeutic effect. )n cases of-local administration or solctivo uptake, the effe:ivc koel ccncentraioi of te compounds may not be related to plasma concentrakin. Ore having skill in the art will be able to optimize therapeutically elective local dosages without -undue exporimentaton. 100461 The amount of CrTmpournd admnlIstered will, of course, be dependent on the subject being treated, on the subject's weIght, the severity-of The affllc-tion, the manner of administration, the frequency u administration and the judgnerit of the prescribing physician. The therapy may be 10 WO 2054117945 PCT1I l')M3)i9674 r ri9e5 ht I a are cetectable or even when they cre not deteteNe, The therapy muay be provided alone gr Irn combInation with other drugs. KIts [00471 The Invention also provides en artcle af m ufacturing comprisng packaging naterMd and a pharrnmeulrA agent cunhairied wiHin there packagIing material, whereir! the pharmiaceutical agent corirlses at-least one IL-1-specific fuslor proten of the inventilon and wherein the packaging maLerial cmprirpses a label or package insert whici indicates that the li-.-spoolfic ruson protein can be used for ?retinH a1 autoinfrnatorydsens or condition. [0048] -Other features of the Invention wPI become appaiert in the course of the following descriptions of oxemplry ermbodirmniits which ire given for illustration of the Invenuon and are not intended to be limiting thereof. EXAMPLES [0 0 4 9 ] The following example Is put forth so as to proVde those of ordinary skill In the art with a cornpiete disclosure and description of howto makeo.nd uas the methods and compositionof the invention. and-are not intended to limit the scope of what the Inventors regard as their Itivontlon. Efforts have been maee to ensure acuracy with respect to nunibi2s Used (C., arnounts, temperature, etc) but some experimental errors and -deviatons should be accounted for. Unless indicated otherwise, patis are parts by weight, mleuLUlar weight is average molecular weight. temperature Is in degrees Centigrade, and pressure is at or near atmospheric. Example 1. Effect of IL-1 Trap on Human Autonflammatnry Dsasme. [0050] An initial study is conducted with 15 adult subjects suffering from discasos known to respond to iL-1 blockade (NOMiD/MWS/FCAS) as well as subjects with Adult -StIl disease and colonicina-rosistant MPF. Subjects are ocroonod for oligibilty, cIlnical symptoms dWermined, active-disease confirmed and baseline blood a3 drawn on approxmately 3 occasions one waek apart to determine baseline levels of inlmaton. A careful. complete stand ardized history. and physical exam is performed, appropriate for the disease Under Study tcrassure- uniform data collection on every sLibject. Vital sigis a nd weight is obtained at each visit. The clirical data IS based on a detailed questionnaire including all tho roperted clinical mranlfestations. The following evaludLian procedures pertain specifically to CIAS-i ntuiation associated disurders and at performed as cliniealy indicated: dermatological evaluation; ophthsliroicc evaution; earoselbroat.evaluaon; neurology evMavtion; lurbar procture; head MRI; radiographs, joint MR; and pharmacokinetic profflIng. [0061] All study subject's receive IL-1-blnding tsion proteIn (SEQ ID NO:10) with a dung rugnIen of I O mg once a day for 3 consecutive days, a rgirnen expected to provide 2-4 weeks of significant IL-1 inhlbItory.aciUIy. The primary outcomes re measured during this nerod and inpluds drug safety, glinioal efficacy analysis, and the ohange !n selected blornarkers of 11 WO 2005/117WS PCT/L| S25 /U19674 lnflL9rflidn , 14A &nts such as CRP, serum amyinid A, and ESR) at Day 10 following irntiation of treatment with IL-1 trap, If a favorble response k observed at Day 10, subjects aro monitored at predefined tirnepoints (with no-further treatment) until return ot-sigrs and syriiptoms (flar j. odn fiare, subjects-re lcgIbletfr edftyInt in dxndrisdn phase thit citails re-treatment wth the loading regImer (100 mg/day IL- trap for three consecutIve days) followed by once-weekly dosing With 100 ig IL-1 trap fr lip to onD year. [00521 -Based on the Invsstlgair's cinica judgment, an I.-I trap dose escalation regimen may be Implemented If, after 4 woks.o dosng in tho extension phase at 100 mg/week, a subject's Month 1 noute phase reactant Ievels have not nonimalied (CRIP > 0.5 mg/dlL and/oi SAA> 10 mg/L) or e.salation.ls wan-anted based on perslstent elgors andtor symptoms of disease, The first dose escalaton levpl may be 16 s.c. once weekly. Subjects will be obsered for 4 weeks; it crteiia for-dose escalation are sfil met, then the dose may be raised to 420 mg s.c. once weekly. [0053] PrejirnI s Four subjerAs wilt CAPS were iniiAll unrolled, Rrsuhs indluated tht all objects eperenced ripid and extensive imprvrtaeri In influrriatory sighS and symptoms upon treatment with IL-1 trap (SEQ 10 NO:10), including rmprovament in both patient and physician- repirtsd disease manifestation. Major declines in Inflammatory blonmarkeM, stch as CRP and SAA were elsc observed. Signs and Symptoms retLmesd wIthin a rnedian of 21 days (range 0-26) of initial dosing and then responded promptly to re-treatment. Table I provIdes a surrmary of-the daily ilary -scores actte ph-5se reactants and cin;cal assessments Ct Performed on 3 patients; * stabstically significant difference from previous time point Fit p < 0.1 lM; " stalsilEcally sCgrfcant differerie from prevIous time poInt at p < 0.05 [evol). The PhysicIan and Patient global assessnient VAS scores mirrored the changes In the acute phase reactants (SAA, CRP and ESR) at baseline, ;A the time of flare, and -it a time point designated as reflecting maximal efficacy.

WVO 20 77/ V945 C'U20. 9074 TwUle 1 Baseline jMnlnmiall EfficacyFlr rnedan (range) :1 median rangee) rtedar, (iange ) Daily Diary SnreT 6A36 (2.2-7 58) 1.07 (O.3YV 44~ (2--3Sa) Acute phase rezacants BAA (ngflL) 08 (1i6A -46 ).26 (2-10) 84 (50-286)t CRP (mg/dL) 7.28 (2.32-8.65) 9.12 (0-07115)- 2.93 (%076-6.2-1) SR (rv1wi) .50.107 (22-92) . 24 %745)*W 34 ( .7~ wEC3 1l5.28(3194 7.I5B(7.21 .9)x 8.48 (&3V1 147) Hgb t2,95 (8.1-1't7) 18.3 (aA r 13.1 (7.R.14.57) flL ~S3.5 (291-445.5) 303.25 (240-377)-I 29-M 735.) (Cm) 6.35 (4169) 0.2 (0.2-2.6) 3.5 (3.1-3.5) patIerl gjobal VAS (Ln) 1 5-.2 (3 9M-6.9) 1.1 (O?..35)" -( - 5* -Ague VAIS (CmFr) 6.65 (3v 28) I 5 pQ.5-8.g) 5(.569 Pal i VAS (orn) 7,55 (3-.77 0-95 (0-2-l.05y .4.1 (0.5-6.55i) Sr-so Pliclal Health 44.38~ 142-5A7.5) 5.33561) 41,50 (35-09,4' SFs ena eakh 41.625 (28.5-57,B) 75.8 (55-96) 39 6r: (37-57) ... 1 3.......

Claims (5)

1. An interleukin 1 (IL-1) fusion protein antagonist comprising the amino acid sequence of SEQ ID NO:10, 12 or 14, for use in a method of treating, inhibiting, or ameliorating 5 Neonatal Ohset Multisystem inflammatory Disorder (NOMIDIGINCA), Muckle-Wells Syndrome (MWS), Familial Cold Autoinflammatory syndrome (FCAS), familial Mediterranean fever (FMF), tumor necrosis factor r.eceptor-associated periodic fever syndrome (TRAPS), or systemic onset juvenile idiopathic arthritis (Still's Diseaso); dridlor an autoinflammatoly disorder, disease, or condition that is associated. with a rntatioh h CIAS-1, whciin tho IL-1 10 fusion protein antagonist is administered in a dose range of 100-320 mg on a weekly basis.

2. An interleukin-1 (IL-1) fusion protein antagonist as defined in claim i as a first therapeutic agent for administration in a dose range of 100-320 rmg on a weekly basis, 15 and of one or more further therapeutic agents selected from an iL-I fusion protein which is different from the first therapeutic agent, etanercept (Enbrel®, Amgen), infliximab (Remicade., Centocor), Humira@ (Abbott), thalidomide, a steroid, anakinra (Kinaret, Amgen), colchicine, IL-18BP or a derivative. an IL-18-binding fusion protein, anti-IL-I, anti IL-18R1, anti-iL-18Raop, aspInri, prednisolone, methotrexate, cyclosporine A, caspase-l, 20 p38, IKKl/2, CTLA-41g, anti-iL-6 2nd anti-IL6Ra for use in a method of treating, inhibiting, or ameliorating Neonatal Onset Multisystem Inflammatory Disorder (NOMID/CINCA), Muckle-Wells Syndrome (MWS), Familial Cold Autoinflammatory syndrome (FCAS), familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic. fever syridonie (TRAPS), or systemic onset juvenile 25 idiopathlc arthritis (Still's Disease): and/or an autoinflammatory disorder; disease, or condition that is associated with a mutation in CIAS-1.

3. A product comprising: as a first therapeutic agerit, an interleukin 1 (IL.-1) fusion protein antagonist as defined 30 in claim 1. for administration in a dose range of 100-320 mg on a weekly basis, and one or more further therapeutic agerts: for separate, sirhultanousA or sequential use iM the treatment of a disorder:, disease Or condition of the human or animal body as defined in claim 2. 35 4. A product according to clairi 3, wherein the further therapeutic agent or agents are as defined in claim 2. 14 5, An interleukin-1 (IL-1.) fusion protein antagonist as defined in claim 1 when used for -a method of treating, inhibiting or ameliorating Neonatal Onset Multisystem inflammatory Disorder (NOMID/CINCA), Muckke-Wells Syndrome (.MWS), Familial Cold Autoinflammatory -5 syndrome (FCAS), familial Mediterranean fever (FMF), tumor necrosis factor receptor associated periodic fever syndrome (TRAPS), or systemic onset juvenlie Idiopathic arthritis (Still.s Disease); and/or an autoinflammatory dsorder, disease, or condition that is associated with a mutation in CIAS-1, by co-administrati6n with a further therapeutic ageht as defiried in claim 2, wherein the IL-1 fusion protein ahtagonist is adrministbrod in a dose rarig of 100 -320 10 mg on a weekly basis.

6. A further therapeutic agent as defined in claim 2 for use in a method of treating, inhibiting or ameliorating Neonate Onset Multisystem Inflarmmatory Disorder (NOMI D/CINCA), Muck:le-Weils Syndrome (MWS), Familial Cold Autoinflammatory svndronie

15- (FOAS), familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS), or systemic onset juvenile idiopathic arthritis (Still's Disease); and/or an autoinflammatory disorder, disease, or condition that is associated with a mutation in CIAS-1, by co-administration with an interleukin-I (IL-1) fusion protein antagonist as defined in claim 1, wherein the IL-1 fusion protein antagonist is administered in a dose 20 range of 100-320 mg on a weekly basis. 7. An IL-1 fusion protein antagonist-or a further therapeutic agent according to any one of claims 1, 2, 5 and 6, wherein the fusion protein -antagonist is administered at a dose of 100 mg, 1.60 mg, or 320 mg, .on a weekly besis. 25 8. An IL-1 fusion protein antagonist or a further therapeutic agent according to any one of claims 1, 2, 5, 6 and 7, which is for subcutaneous, intramuscular., intravenous. topical, transdermal or oral administration. 30 9. An IL-1 fusion protein antagonist of claim 1, substantially as hereirlbefore described with reference to the T[able and/or Exartles 15 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011 2011224099 16 Sep 2011