HUE030386T2 - Átirányított, genetikailag módosított szabályozó T-sejtek és azok alkalmazása autoimmun és gyulladásos betegség szuppressziójára - Google Patents
Átirányított, genetikailag módosított szabályozó T-sejtek és azok alkalmazása autoimmun és gyulladásos betegség szuppressziójára Download PDFInfo
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- HUE030386T2 HUE030386T2 HUE08728776A HUE08728776A HUE030386T2 HU E030386 T2 HUE030386 T2 HU E030386T2 HU E08728776 A HUE08728776 A HU E08728776A HU E08728776 A HUE08728776 A HU E08728776A HU E030386 T2 HUE030386 T2 HU E030386T2
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- ÁTIRÁNYTFOf T, GENETIKAILAG MÓDOSÍTOTT SZABÂLY01É T-SEJTEK ÉS AZOK ALKALMAZÁSA AUTOIMMUN ÉS GYULLADÁSOS BETEGSÉG SZÖFFEESSZIÓJÁRA Szabadalmi Igénypontok L Szabályozó (regulatőrikus) fenotipussal rendelkező átirányított T~Umfociták (átiíónyííöít T-sejtek) populációja, ahol az átirányítok T-sejtek spécificítássai rendelkeznek egy target (cél) antigénnel vagy Ugandámmal szemben, amely target (cél) antigént vagy Sigandumot egy olyan képezi, amely egy nem kívánt immunválasz vagy gyulladásos válasz egy helyén vagy szövetéhen van jelen vagy van expresszit! va, amely sejtek mind tartalmaznak egy kiméra nukkinsav·molekulát, amely expresszi!, egy egyedüli, folytonos láncban, egy kiméra receptor pöl í pepiidet* amely tartalmaz egy extraceíluláris felismerő régiót (angolul: „extracellular recognition region''), egy transzmembrán régiót (angolul: „transmembrane region") és egy intraeeliuíáris jelátviteli régiót (angolul: „intracellular signaling region5''), olymódon, hogy annak az extraceíluláris régiója a nevezett sejteknek a felületén van megjelenítve, ahol a nevezett kiméra nukieinsavrtnolektila a következőket tartalmazza: (a) egy első nukleinsáv-szegmenst, amely tartalmaz egy szekvenciát, amely kódolja a nevezett extraceíluláris felismerő régiót, amely specifikus a nevezett target (cél) antigénre vagy Ugaodumra, amely régió nem tartabnaz egy MBC-protein extraceíluláris domént; és ahol a nevezett régió a target (cél) antigénhez vagy ligandumhoz egy nem MBC által korlátozott módon vagy az MBCMól nem függő módon kötődik; (b) egy második uukfcinsav-szegmensi, amely tartalmaz egy szekvenciát, amely .kódolja a nevezett transzaié rnbrán régiót; és (c) egy harmadik nukleinsáv-szegmenst, amely tartalmaz egy szekvenciát, amely kódolja a nevezett íntraeeikdúris jeíátvitelí régiót, amely mrtäirnazzä T-sejt jelátviteli pokpeptklmioíekukuvszekegy kombinációját, L Átirányított T-sejtek populációja sz i. igénypont szerint, ahoi a nevezett extraceíluláris felismerő régió a target (cél) antigénhez vagy Ugandámhoz oly módon kötődik, hogy az függetlenül történik egy kost! múl adós íigandumnak egy target teéí) sejthez történő kapcsolódásától, T Átirányított T-sejtek populációja az 1-2. igénypontok bármelyike szerint, almi a nevezett extraeelluláris felismerő régió tartabnaz egy antitestből származó scFs-domeítt, amely specifikus á target foci) antigénre vagy ligandumra. #, Átirányított T-sejtek populációja az 1-3, igénypontok bármelyike szerint, ahol a nevezett extraceíluláris felismerő régió össze van kapcsolva a nevezett transz membrán régióval egy flexibilis távtartó tangóiul: „spacer"; révén, előnyösen egy zsanér (angolul: „hinge5'} révén az unmunglobulin-szupercsalád egy molekulájából. i„ Átirányított T-sejtek populációja az 04. igénypontok bármelyike szerint, ahol a nevezett intraeeliuíáris régió tartalmaz egy jelátviteli moiekularészt a következőkből: (i) egy T-sejt egy antigén-specifikus receptorának egy poiipeplid-iánca és/vagy (ti) egy T-sejt egy receptorának egy polipeptid-látiea. amely tartalmaz egy régiót, amely tartalmaz egy inmumreeeptor tirozin-alapú aktivációs motívumot íR'AM), előnyösen egy jelátviteli rnoiekuSurészt egy poHpeptíd-láncból, amely a következőkből álló csoportból van választva: a TCR/CD3-komplex egy lánca és egy ïgFc-meeptornak a y-lánca fFcRy). 6( Átirányító« T-scjiek populációja az 1-5, igénypontok bármelyike szedni, ahol <i nevezett int race iluláris régió tartalmazza egy T-sejt kostimulócíós receptor protein egy jelátviteli molekularésxeL előnyösen legalább egy proteint, a következőkből álló csoportból xaiav/iva C f » 'S, O\40, CDIOI, a-iBB (í 0137) ex PÍM. % Átirányított T-sejtek populációja az 1-6. igénypontok bármelyike szerint, ahol a nevezett :ímracelluláris jelátvitelt régió tartalmaz cgv jelátviteli enzimet, amely (a) egy enzim egy T-sejt egy antigén-specifikus receptorának a jelátviteli útvonalán vagy (b) egy enzim, amely megfelelő speeiíseifássn! és aktivitással rendelkezik, mint az ta) szerinti enzim, és amely egy nem T-seit-hmfociíából, előnyösen a Syk-kiná/. család egy tagjából, származik. 8» .Átirányított T-sejtek populációja az. 1-7, igénypontok bármelyike szerint, abc! a nevezett kirnéva nukleinsav továbbá tartalmaz egy nukleotid-szekvcnciát, amely kódolja az FoxP3-at, ami Mi okozza, hogy az átirányított Treg expesszálja az I~öxp3-at, f* Átirányított T-sejtek populációja igénypontok bármelyike szerint, ahol a nevezett target (cél) antigént vagy liganduntoí egy olyan képez.!, amely egy olyan autoimmun válasz, vagy gyulladásos valasz egy helyén vagy target (cél) szövetében van jelen vágy van expresszáíva. amely autoagresszív effeklor T-scjtck által van közvetítve. Ü* átirányított T-scjtek populációja az 1-9. igénypontok bármelyike szerint, ahol o nevezett autoimmun válasz vagy gyulladásos válasz és a nevezett target (cél.) antigén vagy llgandum a kővetkezőkből álló csoportból vannak választva: (a) gyulladásos bélbetegség (I.BDi, ahol a nevezeti antigént vagy Iigandumot egy olyan képezi, amely a megbetegedett vastagbélben vagy csipőhéiben (ileumban) van expresszáíva; (b) reumatoid artritisz, ahol a nevezett antigént vagy iigandumotegy kollagén opliőp képezi vagy egy antigén, amely m Ízületekben van jelen; (c) s/klerózis multiplex, ahol & nevezett antigént vagy Itgandumot egy neuronais antigén képezi; (d) autoimmun; íirokiísz (pajzsiningy-gytdladás). ahol a nevezett antigént vagy Iigandumot egy tinóid ípajzsroirigy) antigén képezi; (e) autoimmun gasztritísz, ahol a nevezett antigént vagy Itgandumot egy gasztrikus antigén képezi; (f) autoimmun uveitisz vagy nveoretínittsz, áhoi a nevezett antigént vagy Itgandumot S-antigén vagy egy más uveális vagy tetináíls Mtigésképezí; (g) aüíotmimun orhitísz (heregynlíadás), ahol a nevezett antigént vagy Iigandumot egy tesztikuíáris (here) antigén képezi; (h) autoimmun ooíbritisz (petefészek-gyulladás), ahol a nevezett antigént vagy Itgandumot egy petefészek antigén képezi; (i} pszoriázis, ahol a nevezett antigént vagy Iigandumot égy kemtínocita antigen vagy egy más dermáhs vagy epidennális antigén képezi; (j) vttigö* ahőí a nevezett antigént vagy Itgandumot egy otelanöeita antigén képezi; (k) autoimmun prosztatitisz (prosztata-gyulladás), ahol a ne\ e/ed antigént vagy Iigandumot egy prosztata amigén képezi; (l) bármilyen nem kívánt immunválasz, ahol a nevezett antigént vagy Iigandumot egy aktivációs antigén képezi, amely effektor T-sejteken van expresszalva,; amelyek a nem kívánt immunválasznak a helyén vannak jelen:; ím) szövet kilökődés, ahol a nevezett antigént vagy ligandumot. az MHC-ntoíeknía képezi, amely rendelkezik a transzplantáit tátültetett) szövetnek a haplotípusávai, vagy annak az MHC·molekulának egy része képezi; éti) egy gyulladásos állapot, ahol a nevezett antigént vagy lígandumot egy olyan képezi;, amely a hemopoeiikus sejtvonal nem-liratbid sejtjein van expresszálvá, amelyek közreműködnek a gyulladásban.
- 11. Immnnszabályozé gyógyászati készítmény egy immun/gyuíladásos válasz szuppmssztájáka vagy egy itntnun/gyuUadásos hetegslg vagy alapot kezelésére, amely a következőkét tartalmazza; (i|: átinányított T~sejtek egy populációját az 1-10, igénypontok bármelyike szorisn, és (h) egy győgyászatilag és imtnunológiailág elfogadható hordozót, segédanyagot (excípienst) vagy higítószert.
- 12. Eljárás az 1.-10. igénypontok bármelyike szerinti átirányítóit T-sejtek populációjának az előállítására, amely magában foglalja a következő fa) - (d) lépéseket: (a) iimibeiíáh vagy T-sejtek egy populációjának a rendelkezésre állítása, amelyek egy alanyból vannak kapva, és opeiopálisan a iímfoeiíák vagy T-sejtek nevezett populációjának a dúsítása vagy izolálása és szaporítása; (b) egy Treg-sejt-íenotípus indukálása a nevezett sejtekben azáltal, hogy a sejtek megfelelően vannak stimulálva vagy aktiválva azáiiak hogy a TGF~ß--nak vagy más citokinnak vannak kitéve, amely indukálja az pozpB-expressztöt, ami által indukálva van a Treg-ienotípus; (e) a t b) lépés előtt vagy után, a sejtek er vívó transzíekeíója vagy transzüukdója egy expressziős vektorral, amely kódolja a nevezett kiroéra receptort, amely a nevezeti T-sejteken történő expresszálásra van szánva; és Cd) opcionálisan, a fentiek szerint kapott sejtek in vitro tenyésztése vagy expandálása, vagy magában íógláljá a következő (e) - (h) lépéseket: (e) Iímfoeiíák vagy T-sejtek egy populációjának a rendelkezésre állítása, amelyek égy alanyból vannak kapva, és opcionálisan íimíooíták vagy T-sejtek egy populációjának a dúsítása vagy .izolálása és szaporítása; (íj a sejtek nr vivo trans/.tekeiőja vagy trunszdukdóju egy vektorral, amely kódolja a kíméra receptort; (g) az ff) lépés előtt, után vagy azzal egyidejűleg a sejtek ex vivo transzfekciőja vagy transzdiíkeiöja egy rekombínáns nukleinsav expresszié« konstrukcióval, amely kódolja az Foxp3-at; és (h) opcionálisaikapott sejtek in vitro tenyésztésé vágy expandálása.
- 13. Átirányított T-sejtek populációja az 1-11) igénypontok háimeivtke s/eruit, amely cg> hatásos .mennyiségben áll rendelkezésre, alkalmazás céljából egy eljárásban, amely egy immunválasz vagy gyulladásos válasz közvetítésére szolgál, vagy egy immm'i/gytdladásos betegség vagy állapot tüneteinek a kezdése vagy javítása során eg> emlős alanynál, azáltal, hogy a szuppressziőra szánt effektor T-sejtek egy helyére van juttatva a nevezett Treg-sejtek egy mennyisége, amely hatásos abban, hogy a nevezett effektor T-sejt aktivitás szuppreszzáiva legyen. 14*. Átirányított. T-sejtek populációja alkalmazás céljából a .13. igénypont szerint, egy munun/gyulladásos betegség vagy állapot tüneteinek a kezelésére vagy javítására egy emlős alanynak amely effekíor T~ sejtek nem kívánt aktivitása által van közvetítve, ahol a? továbbá magában foglalja azt, hogy, vagy az átirányított Treg-sejtek adagolása előtt, vagy azzal egyidejűleg, vagy az után, egy e.xogén antigén vagy Hg andern van eljuttatva a nevezett immunválasz vagy gyulladásos válasz egy helyére vagy target (cél) szövetéhe, és ahol a nevezett target (cél) antigént vagy ligundumot a nevezett exogen antigén vagy ligandum képezi. IS, Kiméra DNS-unolekula, amely a következőket tartalmazza: (a) egy első nukleinsav^szegmensl, amely tartalmaz egy szekvenciát, amely kódol egy ©xtraeelluiáris relismctő régiót, amely specifikus egy target (cél) antigénre vagy ligandumra, amely régió nem -tartalmaz egy MllC-protéín 'ex£raee!lu!ári§. domém, és afedi a nevezett régió a nevezett target feil) antigénhez vagy Ugandámhoz égy nem által korlátozott módon vagy az MHCbtől nem függő módon kötődik; ahol a nevezett antigént vagy ligandumot égy olyan képezi, amely egy item Mvirtt hntnunMiasz vagy gyulladásos válasz égy helyén vagy szövetében van jelen vagy van expre.sszálva; (b) égy második nuklemsav-szegmenst, amely tartaimaz egy szekvenciát, amely kódol egy iranszmembräp régiót; (c> egy harmadik nukleinsav-szegntensk amely- íattalmaz egy szekvenciái:, amely kódol egy ínírucclluláris jelátviteli régiét, amely Mríaímazza Ibsejí jelátviteli polípeptid-molekularészek egy kombinációját, és (d) egy nukltíotid-szekvenciát. amely kódolja az FoxpSmh ami a kiméra nukiéiMavv molekulának egy T-sejtbe történő transzíékciőja vagy transzduketója mellett (után.} azt okozza, hogy a transz feküdt vagy ttapszdukált T-scjt expesszalja az Foxp3-at. ahol, a kunéra nukleinsav-rnolrkníának egy T-sejtbe. történő tragszfokciója vagy transzdukdója mellett (után), aT-sejt expr esszál egy kiméra receptor polipepiidet, amely tartalmazza a nevezett ox trace! inkiris felismerő régiót {angolul: „extracellular recognition region"}, a nevezett transzrnemhrán régiót (angolul: ,dfansmembrane region'*} és a ueve/ett intracellnlaris jelátviteli régiót (angolai: „intracellular signaling régiöíi,*'k egy egyedüli, folytonos láncban, ahol a T-sejt megjeleníti az ex trace! iul ária régiót a sejtfehlieten& ©xpresszálja az Foxp3-at, ami állal egy átirányított 'íbMíufoetta les/, amely Treg-sejPíénofípttssal rendelkezik, ífo Kiméra BMiémöíekula a 15. igénypnt szerint, ahol a nevezett cxtraeeíluláris Mismefo régió a target (cél) antigénhez vágy Ugandámhoz oly módon kötődik, hogy az függetlenül tíÉtémk egy kosttmuiáetös lígandttíonak egy target (cél) sejthez történő kapesolódlsátöL
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