ME01706B - Antitumorska kombinacija koja sadrži vegf-zamku i 5fu ili jedan od njegovih derivata - Google Patents
Antitumorska kombinacija koja sadrži vegf-zamku i 5fu ili jedan od njegovih derivataInfo
- Publication number
- ME01706B ME01706B MEP-2009-272A MEP27209A ME01706B ME 01706 B ME01706 B ME 01706B ME P27209 A MEP27209 A ME P27209A ME 01706 B ME01706 B ME 01706B
- Authority
- ME
- Montenegro
- Prior art keywords
- combinations
- synergistic effect
- treatment
- vegf trap
- fluorouracil
- Prior art date
Links
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Classifications
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Description
Opis
Ovaj pronalazak se odnosi na kombinacije VEGF Zamke i jednog hemotoksičnog agensa klase 5 fluorouracila ili 5 fluoropirimidina koji se koriste u lečenju bolesti neoplastija.
Inhibitori VEGF koji su inhibitori faktora rasta vazikularnog endotelijuma (vascular endothelial grovvth factor) u njavećem broju slučajeva kod bioloških proizvoda odabranih od rastvorljivih receptora, antisensa, i aptameraRNK i antitela. Derivati 5 fluoropirimidina su odabrani od 5-fluorouracila, kapecitabina ili gemcitabina koji imaju značajno antitumoralno i antileukemijsko dejstvo, posebno su korisni u lečenju kancera jajnika, dojke, pluća ili debelog creva. Ova kombinacija se odnosi posebno na iečenje kancera debelog creva ili želudca.
Opis i priprema inhibitora VEFG koji se koristi u pronalasku i koji je hibridni protein VEGF-Zamka, dat je u patentnoj prijavi WOOO/75319. Postoji nekoliko načina za dobijanje hibridnog proteina. Način dobijanja koji odgovara VEGF-Zamci je onaj opisan na slici 24 (sckvenca). VEGF Zamka koja se koristi u ovom pronalasku je protein fuzionisane sekvence signala VEGFR1 sa domenom Ig D2 receptora VEGF1, koji je i sam fuzionisan za domen Ig D3 receptora VEGFR2 fuzionisan sa svoje stane sa domenom Fc iz IgGl koji se joiš zove VEGFRlR2-FcACl ili FltlD2. FlklD3. FcACl.
Uopšteno doze koje se koriste, koje zavise od predmeta lečenja, su između 20 i 800 mikrograma po kilogramu kada se davanje vrši subkutano i 2 do 20 mikrograma po kilogramu kada se davanje vrši intravenozno ili eventualno intranazalno u dozi koja je manja od reda veličine 0, 01 pikograma do 1 mg po kilogramu.
5-fluorouracil se u glavnom koristi intravenozno u dozi između 500 mg/m2 i 5000 mg/m2 nedeljno a što se tiče derivata 5-fluoropirimidina kao što je kapecitabin on se koristi uglavnom oralno u dozi između 500 i 3000 mg/m2 koja je raspoređene u dve dnevne doze. Gemcitabin se koristi najčešće intravenozno u dozi između 500 i 2000 mg/m2 nedeljno.
U članku H. Hunvitz, L Fehrenbacher, W Novotny, T Cartvvright, J Hainsworth, W Heim, J Berlin, A Baron, S Griffmg, E Holmgren, N Ferrara, G Fyfe, B Rogers, R Ross, F Kabbinavar u "The New England Journal of Medecine" opisano je kliničko ispitivanje koje potvrđuje korisnu upotrebu kombinacije bevacizumaba sa irinotecanom, 5Fu i leucoveurinom u odnosu na istu kombinaciju koja ne sadrži bevacizumab. U ovom kliničkom ispitivanju nema ničega što dokazuje da se postizanje cilja dobija kombinacijom 5FU i bevacizumaba, može se zaključitiu takođe da je to kombinacija irinotecana ili leucoveorina sa bevacizumabom ili kvatemerna kombinacija ta koja da je rezultat. Takođe je poznato da svaki antikancerogeni agens pored svojih antikancerogenih efekata ima i sekundarne toksične efekte te se čini oportuno podići njihovo prisustvo do maksimuma ako se isti efekat može postići i bez najmanje jedne od navedenih komponenti. U ovom slučaju je poznato da irinotecan izaziva značajne dijaree koje je nekad nemoguće zaustaviti tokom tretmana. S druge strane ovaj članak ne dokazuje nijedan sinergijski efekat u smislu Corbett tj. efekat koji ne bi bio postignut ukoliko bi se svaka od komponenti iz kombinacije davala pojedinačno u svojoj maksimalno tolerisanoj dozi.
Sada je pronađeno, što čini predmet ovog pronalaska, da efikasnost VEGF Zamke može znatno da se poboljša ukoliko se da je u asocijaciji sa najmanje jednim derivatom 5-fluorpirimidina (supstance koja se koristi u lečenju kancera i koja ima drugačiji mehanizam od inhibitora VEGF)
Pre svega, aktivnost proizvoda zavisnih od upotrebljenih doza, moguća je upotreba povećanih doza i porast aktivnosti i smanjivanje toksičnih pojava i njihovo odlaganje njihovog pojavljivanja asocijacijom sa VEGF Zamkom, drugim supstaneama koje su terapeutski aktivne kod faktora rasta tipa hematopoeznim kao što su G-GSF ili GM-CSF ili određeni interleukini.
Posebno, ovaj pronalazak se odnosi na asocijaciju VEGF Zamke sa 5 fluorouracilom ili njegovim derivatima kao Što su kapecitabin ili gemcitabin. Takođe se odnosi na kombinaciju koja uključuje još i folnu kiselinu koja je generalno u asocijaciji sa 5-FTJ.
Povećana efikasnost kombinacije prema pronalasku može se očitovati determinisanjem terapeutskog sinergizma.
Jedna kombinacija pokazuje terapeutski sinergizam ukoliko je terapeutski superiorna od pojedinačnih komponenti koje se koriste u svojim optimalnim dozama [T. H. CORBET et coll., Cancer Treatment Reports, 66, 1187 (1982)].
Kako bi se prikazala efikasnost jedne kombinacije, može biti neophodno da se uporede maksimalne tolerisane doze kombinacije sa maksimalnim tolerisanim dozama pojedinačnih konstituenata. Ova efikasnost se može meriti, na primer kao log10 ubijenih ćelija koje se defmišu na sledeći način:
Log10 ubijenih ćelija = T-C (dana)/3. 32 XTd u kojoj T-C
predstavlja razliku između ćelija koja je srednje vreme, u danima, koje je potrebno da tumori kod tretirane grupe (T) i tumori kod uporedne grupe (C) ne dostignu prethodno definisaniu vrednost (1 g na primer) i Td predstavlja vreme, u danima, potrebno za dvostruko uvećanje zapremine tumora kod životinje koja je uporedna [T. H. CORBETT et coll., Cancer, 40, 2660. 2680 (1977); F. M. SCHABEL et. coll., Cancer Drug Development, Part B, Methods in Cancer Research, 17, 3-51, New-York, Academic Press Ine. (1979). Jedan proizvod se smatra da je aktivan ukoliko logio ubijenih ćelija je veći ili jednak sa 0, 7. Jedan proizvod se odnosi kao veoma aktivan ukoliko log10 ubijenih ćelija je veći od 2, 8.
Kombinacija, koja se koristi u svojoj maksimalnoj tolerisanoj dozi, gde svaki od konstituenata je prisutan u dozi dozi koja je generalno manja od njegove pojedinačne maksimalne tolerisane doze, pokazuje sinergijski terapeutski efekat kada logio ubijenih ćelija je veći od vrednosti logio ubijenih ćelija od najboljeg konstituente kada se da je sam.
Efikasnost kombinacija na čvrstim tumorima može se determinisati eksperimentalno na sledeći način:
Životinjama koje se podvrgavaju eksperimentu, najčešće miševima, su nakalemljeni bilateralno subkutano 30 do 60 mg fragmenata tumora dojke MC 13/C na dan 0. Životinje nosioci tumora su raspoređene kako bi primile različite tretmane i bile kontrolisane. Ukoliko se tumor primio, ostavi se da naraste do željene veličine, životinje kojima tumor nije dovoljno narasta se eliminišu. Odabrane živorinje se takođe po sistemu slučajnog uzorka uzimaju za dalji tretman i kontrolu. Životinje koje nisu nosioci tumora mogu se takođe podvrgnuti istom tretmanu kao i životinje nosioci kako bi se mogao razdvojiti toksični efekat od čistog efekta na tumor. Hemoterapija započinje 3 do 22 dana nakon kalemljenja tumora u zavisnosti od tipa tumora i životinje se posmatraju svaki dan. Različite grupe životinja se markiraju tri ili četiri puta nedeljno sve do maksimalnog gubitka težine zatim se markiraju najmanje jedanput nedeljno do kraja ispitivanja.
Tumori se mere dva ili tri puta nedeljno sve dok tumor ne dostigne oko 2 g ili do smrti životinje ukoliko se ovo dogodi pre nego što tumor dostigne 2g. Izvrši se autopsija na životinjama nakon žrtvovanja.
Antitumorska aktivnost se determiniše u funkciji različitih registrovanih parametara.
Za proučavanje kombinacije na leukemiji, na životinje se kalemi određeni tj. determinisani broj ćelija i antitumorska aktivnost se determiniše porastom vremena preživljavanja miševa tretiranih u odnosu na kontrolne. Jedan proizvod se smatra za aktivan ukoliko produženje vremena preživljavanja je veće od 27% i smatra se za veoma aktivno ukoliko je veće od 75% u slučajevima leukemije P388.
Kao primer, dati su, u sledećoj tabeli rezultati dobijeni sa kombinacijom VBFG Zamka i 5-fluorouracil korišćeni u svojim optimalnim dozama.
Ovaj pronalazak se podjednako odnosi na farmaceutske oblike koji sadrže kombinacije prema pronalasku.
Proizvodi koji su konstituenti kombinacije mogu se davati simultano, odvojeno ili razdvojeno u vremenu kako bi se postigao maksimalan efekat kombinovanja; svako davanje može da varira vremenski u zavisnosti od načina davanja koje može biti brzo ili kontinualna perfuzija.
Tako, prema ovom pronalasku, kombinacije nisu samo ograničene na one koje su dobijene fizičkom asocijacijom komponenata, već se komponente mogu vremenski odvojeno davati ili simultano ili vremenski razdvojeno.
Jedinjenja prema pronalasku su najpoželjnije u obliku za parenteralno davanje mada se mogu davati i oralno.
Farmaceutski oblici za parenteralno davanje su obično rastvori ili sterilne suspenzije farmakološki prihvatljive koje se eventualno mogu pripremati neposredno pre upotrebe. Za đobijanje ne vodenih rastvora ili suspenzija mogu se koristiti prirodna biljna ulja kao recimo maslinovo ulje, susamovo ulje, parafinsko ulje ili organski estri injektibilni kao stoje etil oleat. Vodeni sterilni rastvori mogu da se sastoje od rastvora proizvoda u vodi. Vodeni rastvori koji bi bili adekvatni za intravenozno davanje gde je pH podešen tako da je izotoničan, prave se na primer sa dovoljnom količinom natrijum hlorida ili glukoze. Sterilizacija se može obaviti zagrevanjem ili na neki drugi način koji ne utiče na jedinjenja. Kombinacije se mogu praviti i u obliku lipozoma ili u obliku asocijacije sa nosačem kao što su ciklođekstrini ili polietilenglikoli.
U kombinacijama prema pronalasku gde primena konstituenata može biti simultana, odvojena ili vremenski udaljena, naročito je pogodno da količina derivata VEGF Zamka predstavlja 2 do 80% težinskih delova kombinacije što zavisi od prirode supstance koja još ulazi u asocijaciju, željene efikasnosti i prirode kancera koji se tretira.
Kombinacije prema pronalasku su posebno korisne u lečenju kancera debelog creva i/ili želuca. Posebno, imaju prednost u tome da se konstituenti mogu koristiti u manjim dozama od onih koje se daju kada se upotrebljavaju sami.
Sledeći primer ilustruje kombinaciju prema pronalasku.
PRIMER
Prema uobičajenim metodama, za subkutano davanje, pripremaju se ampule od 1 cm3 koje sadrže 25 mg VEGF Zamke koje se razblaže u fosfatnom puferu.
Prema uobičajenim metodama, za intravenozno davanje 0, 2 ml po mišu počevši od komercijalne doze od 5 cm3 koji sadrži 250 mg 5 FU razblažen sa glukozom 5% u vodi.
Ovi rastvori se daju simultano, nakon prigodnog razblaživanjaperfuziono.
Tretman se može ponoviti nekoliko puta dnevno ili tokom nedelje do delimične remisije ili totalne ili ozdravljenja
Claims (7)
1. Kombinacije koje imaju sinergijski efekat koje sadrže VEGF Zamku sa najmanje 5-fluorouracila ili jedan derivat 5 fluoropirimidin za upotrebu u tretmanu neoplastijskih bolesti.
2. Kombinacije koje imaju sinergijski efekat koje sadrže VEGF Zamku sa 5-fluorouracil ili kapecitabin ili gemcitabin.
3. Kombinacije koje imaju sinergijski efekat koje sadrže VEGF Zamku safluoracilom.
4. Kombinacije koje imaju sinergijski efekat za upotrebu prema zahtevu 1 gde kombinacije imaju sinergijski efekat prema zahtevima 2 i 3 karakteristične po tome što između ostalog sadrže folnu kiselinu.
5. Kombinacije koje imaju sinergijski efekat prema zahtevima 1 i 4 gde kombinacije imaju sinergijski efekat prema zahtevima 2, 3 i 4 karakteristične prema tome što sadrže 2 do 80% težinskih delova VEGF Zamke.
6. Kombinacije koje imaju sinergijski efekat prema zahtevima 1, 4 i 5 ili kombinacije prema zahtevima 2, 3, 4 i 5 koje sadrže VEGF Zamku sa 5-fluorouracilom ili derivatom 5 fluoropirimiđina i folnu kiselinu uz izuzetak drugih hemotoksičnih derivata, koje imaju sinergijski efekat u lečenju neoplastijskih bolesti.
7. Proizvodi koji sadrže VEGF Zamku i najmanje jednu supstancu terapeutski korisnu kao što je definisano u zahtevima 1 do 4 u lečenju neoplastijskih bolesti kao kotnbinovani preparat za simultanu upotrebu, odvojenu ili vremenski udaljenu u antikancer terapiji.
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| FR2918279B1 (fr) * | 2007-07-05 | 2010-10-22 | Aventis Pharma Sa | Combinaisons antitumorales contenant un agent inhibiteur de vegf et de l'irinotecan |
| JO3283B1 (ar) * | 2011-04-26 | 2018-09-16 | Sanofi Sa | تركيب يتضمن أفليبيرسيبت, حمض فولينيك, 5- فلورويوراسيل (5- Fu) وإرينوسيتان (FOLFIRI) |
| US9840553B2 (en) | 2014-06-28 | 2017-12-12 | Kodiak Sciences Inc. | Dual PDGF/VEGF antagonists |
| WO2016008975A1 (en) | 2014-07-18 | 2016-01-21 | Sanofi | Method for predicting the outcome of a treatment with aflibercept of a patient suspected to suffer from a cancer |
| KR20250057128A (ko) | 2015-12-30 | 2025-04-28 | 코디악 사이언시스 인코포레이티드 | 항체 및 이의 접합체 |
| EP3246029A1 (en) * | 2016-05-19 | 2017-11-22 | Boehringer Ingelheim International Gmbh | Pharmaceutical combination of nintedanib and capecitabine for the treatment of colorectal cancer |
| US12071476B2 (en) | 2018-03-02 | 2024-08-27 | Kodiak Sciences Inc. | IL-6 antibodies and fusion constructs and conjugates thereof |
| AU2020364071A1 (en) | 2019-10-10 | 2022-05-26 | Kodiak Sciences Inc. | Methods of treating an eye disorder |
| CN115197948A (zh) * | 2021-04-13 | 2022-10-18 | 江苏康缘瑞翱生物医药科技有限公司 | 一种重组新城疫病毒rNDV-VEGF-Trap、其基因组、制备方法及其用途 |
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| US7087411B2 (en) * | 1999-06-08 | 2006-08-08 | Regeneron Pharmaceuticals, Inc. | Fusion protein capable of binding VEGF |
| MXPA01012630A (es) * | 1999-06-08 | 2002-07-22 | Regeneron Pharma | Polipeptidos quimericos modificados con propiedades farmacocineticas mejoradas. |
| AR046510A1 (es) * | 2003-07-25 | 2005-12-14 | Regeneron Pharma | Composicion de un antagonista de vegf y un agente anti-proliferativo |
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