HRP20230050T1 - Polinukleotidi koji kodiraju interleukin-12 (il12) i njihova upotreba - Google Patents
Polinukleotidi koji kodiraju interleukin-12 (il12) i njihova upotreba Download PDFInfo
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- HRP20230050T1 HRP20230050T1 HRP20230050TT HRP20230050T HRP20230050T1 HR P20230050 T1 HRP20230050 T1 HR P20230050T1 HR P20230050T T HRP20230050T T HR P20230050TT HR P20230050 T HRP20230050 T HR P20230050T HR P20230050 T1 HRP20230050 T1 HR P20230050T1
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- Peptides Or Proteins (AREA)
Claims (21)
1. Pripravak za upotrebu u postupku smanjenja veličine tumora ili inhibicije rasta tumora kod subjekta kojem je to potrebno, naznačen time što
(a) pripravak sadrži mRNK koja kodira polipeptid IL-12, pri čemu mRNK sadrži otvoreni okvir za čitanje ("ORF") koji kodira polipeptid interleukina 12 podjedinice p40 ("IL12B") i polipeptid interleukina 12 podjedinice p35 ("IL12A"),
(b) mRNK je formulirana kao lipidna nanočestica koja se sastoji od kationskog lipida, fosfolipida, sterola i PEG-modificiranog lipida, i
(c) postupak se sastoji od intratumoralnog davanja subjektu učinkovite količine navedenog pripravka.
2. Pripravak za upotrebu prema zahtjevu 1, naznačen time što nadalje uključuje davanje subjektu učinkovite količine pripravka koji sadrži mRNK koja sadrži ORF koji kodira polipeptid inhibitora kontrolne točke ili učinkovite količine pripravka koji sadrži polipeptid inhibitora kontrolne točke, pri čemu po izboru
(a) polipeptid inhibitora kontrolne točke inhibira PD1, PD-L1, CTLA-4, ili njihovu kombinaciju; i/ili
(b) polipeptid inhibitora kontrolne točke sadrži protutijelo,
pri čemu je dalje po izboru protutijelo anti-CTLA-4 protutijelo ili njegov fragment koji veže antigen koji specifično veže CTLA-4, anti-PD1 protutijelo ili njegov fragment koji veže antigen koji specifično veže PD1, anti-PD-L1 protutijelo ili njegov fragment koji veže antigen koji specifično veže PD-L1 ili njihova kombinacija;
pri čemu, dalje po izboru, anti-PD-L1 protutijelo atezolizumab, avelumab ili durvalumab; anti-CTLA-4 protutijelo je tremelimumab ili ipilimumab; anti-PD-1 protutijelo je nivolumab ili pembrolizumab;
i/ili
(c) pripravak prema zahtjevu 1 zaseban, ili u kombinaciji s pripravkom koji sadrži mRNK koja sadrži ORF koji kodira polipeptid inhibitora kontrolne točke ili pripravak koji sadrži polipeptid inhibitora kontrolne točke koji aktivira T stanice u subjektu.
3. Pripravak za upotrebu u postupku (i) aktiviranja T stanica kod subjekta kojem je to potrebno, (ii) povećanja omjera T stanica efektora i supresora u tumoru subjekta kojem je to potrebno, (iii) povećanja broja aktiviranih stanica prirodnih ubojica (NK) u subjektu kojem je to potrebno, i/ili (vi) povećanja unakrsnog predstavljanja dendritičnih stanica u tumoru subjekta kojem je to potrebno, naznačen time što
(a) pripravak sadrži mRNK koja kodira polipeptid IL-12, pri čemu mRNK sadrži ORF koji kodira polipeptid IL12B i polipeptid IL12A,
(b) mRNK je formulirana kao lipidna nanočestica koja se sastoji od kationskog lipida, fosfolipida, sterola i PEG-modificiranog lipida, i
(c) postupak se sastoji od intratumoralnog davanja subjektu učinkovite količine navedenog pripravka.
4. Pripravak za upotrebu prema zahtjevu 2(c) ili 3, naznačen time što aktivacija T stanica uključuje induciranje proliferacije T stanica; i/ili pri čemu aktivacija T stanica uključuje induciranje infiltracije T stanica u tumor ili povećanje broja T stanica koje infiltriraju tumor; i/ili pri čemu aktivacija T stanica uključuje induciranje odgovora memorijskih T stanica; i/ili pri čemu aktivirane T stanice sadrže CD4+ T stanice, CD8+ T stanice ili oboje.
5. Pripravak za upotrebu prema bilo kojem od zahtjeva 1 do 4, naznačen time što
(a) primjena pripravka samog ili u kombinaciji sa pripravkom koji sadrži mRNK koji sadrži ORF koji kodira polipeptid inhibitora kontrolne točke ili pripravak koji sadrži polipeptid inhibitora kontrolne točke povećava omjer efektora prema supresoru T stanica u tumoru, pri čemu po izboru omjer efektora prema supresoru T stanica je omjer CD8+ T stanica: T regulacijskim (Treg) stanicama, pri čemu je dalje po izboru omjer CD8+: Treg najmanje 10, najmanje 20, najmanje 30, najmanje 40, najmanje 50, najmanje 60, najmanje 70, najmanje 80, najmanje 90, najmanje 100, najmanje 110, najmanje 120, najmanje 130, najmanje 140, ili najmanje 150; i/ili
(b) primjena pripravka dodatno povećava broj aktiviranih NK stanica u subjektu, pri čemu se izborno broj aktiviranih NK stanica povećava najmanje oko dva puta, najmanje oko tri puta, najmanje oko četiri puta, najmanje oko pet puta, najmanje oko šest puta, najmanje oko sedam puta, najmanje oko osam puta, najmanje oko devet puta ili najmanje oko deset puta; i/ili povećane aktivirane NK stanice se održavaju najmanje oko jedan dan, najmanje oko dva dana, najmanje oko tri dana, najmanje oko četiri dana, najmanje oko pet dana, najmanje oko šest dana, najmanje oko sedam dana, najmanje oko osam dana, najmanje oko devet dana, najmanje oko deset dana, najmanje oko 11 dana, najmanje oko 12 dana, najmanje oko 13 dana ili najmanje oko 14 dana; i/ili
(c) primjena pripravka povećava unakrsno predstavljanje dendritičnih stanica u tumoru subjekta, pri čemu su po izboru unakrsno prezentirane dendritične stanice CD103+ stanice.
6. Pripravak za upotrebu prema bilo kojem od zahtjeva 1 do 5, naznačen time što primjena pripravka smanjuje veličinu distalnog tumora ili inhibira rast distalnog tumora kod subjekta.
7. Pripravak za upotrebu prema bilo kojem od zahtjeva 1 do 6, naznačen time što su polipeptid IL12B i polipeptid IL12A kondenzirani izravno ili pomoću nukleinske kiseline koja kodira poveznicu, pri čemu po izboru
(i) polipeptid IL12B nalazi se na 5' kraju polipeptida IL12A ili poveznice, ili
(ii) polipeptid IL12A nalazi se na 5' kraju polipeptida IL12B ili poveznice; i/ili
(iii) polipeptid IL12B sadrži aminokiselinsku sekvencu koja je najmanje 80%, najmanje 90%, najmanje 95% ili najmanje 98% identična aminokiselinama 23 do 328 iz SEQ ID NO: 48, pri čemu aminokiselinska sekvenca ima aktivnost IL12B; i/ili
(iv) polipeptid IL12A sadrži aminokiselinsku sekvencu koja je najmanje 80%, najmanje 90%, najmanje 95%, ili najmanje 98% identična aminokiselinama 336 do 532 iz SEQ ID NO: 48, pri čemu aminokiselinska sekvenca ima aktivnost IL12A; i/ili
(v) mRNK sadrži nukleotidnu sekvencu koja kodira signalni peptid, pri čemu je izborno signalni peptid IL12B signalni peptid; i/ili signalni peptid sadrži aminokiselinsku sekvencu koja je najmanje oko 80%, najmanje 90%, najmanje 95% ili najmanje 98% identična aminokiselinama 1 do 22 iz SEQ ID NO: 48; i/ili
(vi) ORF kodira polipeptid IL12B operativno vezan preko poveznice na polipeptid IL12A; i/ili
(vii) ORF kodira polipeptid IL12B signalni peptid, polipeptid IL12B, poveznicu i polipeptid IL12A; i/ili
(viii) poveznica sadrži Gly/ Ser poveznicu, pri čemu po izboru Gly/ Ser poveznica sadrži (GnS)m, pri čemu n je 1, 2 3, 4, 5, 6, 7, 8, 9, 10, 15, ili 20 i m je 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, ili 20, pri čemu dalje po izboru Gly/Ser poveznica sadrži (GnS)m, i pri čemu n je 6 i m je 1.
8. Pripravak za upotrebu prema bilo kojem od zahtjeva 1 do 7, naznačen time što
(a) polipeptid IL12 sadrži aminokiselinsku sekvencu koja je najmanje 80%, najmanje 90%, najmanje 95%, ili najmanje 98% identična sa SEQ ID NO: 48;
(b) mRNK sadrži nukleotidnu sekvencu koja je najmanje 60%, najmanje 70%, najmanje 80%, najmanje 90%, najmanje 95%, najmanje 98% ili najmanje 99% identična odabranoj nukleotidnoj sekvenci iz skupine koju čine SEQ ID NO: 5 do 44, 236, i 237;
(c) mRNK sadrži nukleotidnu sekvencu koja je najmanje 60%, najmanje 70%, najmanje 80%, najmanje 90%, najmanje 95%, najmanje 98%, ili najmanje 99% identična sa SEQ ID NO: 236 ili 237; i/ili
(d) mRNK sadrži ORF koji sadrži najmanje jedan kemijski modificirani nukleozid, pri čemu po izboru
(i) najmanje jedan kemijski modificirani nukleozid je odabran iz skupine koju čine pseudouridin, N1-metilpseudouridin, 5-metilcitozin, 5-metoksiuridin, i njihova kombinacija;
(ii) nukleozidi u ORF su kemijski modificirani za najmanje 10%, najmanje 20%, najmanje 30%, najmanje 40%, najmanje 50%, najmanje 60%, najmanje 70%, najmanje 80%, najmanje 90%, najmanje 95%, najmanje 99%, ili 100%; i/ili
(iii) kemijski modificirani nukleozidi u ORF su odabrani iz skupine koja sadrži uridin, adenin, citozin, gvanin i bilo koju njihovu kombinaciju.
9. Pripravak za upotrebu prema bilo kojem od zahtjeva 1 do 8, naznačen time što
(a) uridinski nukleozidi u ORF su kemijski modificirani za najmanje 10%, najmanje 20%, najmanje 30%, najmanje 40%, najmanje 50%, najmanje 60%, najmanje 70%, najmanje 80%, najmanje 90%, najmanje 95%, najmanje 99%, ili 100%;
(b) adenozinski nukleozidi u ORF su kemijski modificirani za najmanje 10%, najmanje 20%, najmanje 30%, najmanje 40%, najmanje 50%, najmanje 60%, najmanje 70%, najmanje 80%, najmanje 90%, najmanje 95%, najmanje 99%, ili 100%;
(c) citidinski nukleozidi u ORF su kemijski modificirani za najmanje 10%, najmanje 20%, najmanje 30%, najmanje 40%, najmanje 50%, najmanje 60%, najmanje 70%, najmanje 80%, najmanje 90%, najmanje 95%, najmanje 99%, ili 100%;
(d) gvanozinski nukleozidi u ORF su kemijski modificirani za najmanje 10%, najmanje 20%, najmanje 30%, najmanje 40%, najmanje 50%, najmanje 60%, najmanje 70%, najmanje 80%, najmanje 90%, najmanje 95%, najmanje 99%, ili 100%; i/ili
(e) mRNK sadrži mjesto vezanja miRNK, pri čemu po izboru
(i) mjesto vezanja miRNK je miR-122 mjesto vezanja; i/ili
(ii) mjesto vezanja miRNK je miR-122-3p ili miR-122-5p mjesto vezanja, ili
(iii) mjesto vezanja miRNK sadrži nukleotidnu sekvencu koja je najmanje 80%, najmanje 85%, najmanje 90%, najmanje 95%, ili 100% identična sa aacgccauua ucacacuaaa ua (SEQ ID NO: 51), pri čemu se mjesto vezanja miRNK veže na miR-122; ili
(iv) mjesto vezanja miRNK sadrži nukleotidnu sekvencu koja je najmanje 80%, najmanje 85%, najmanje 90%, najmanje 95%, ili 100% identična sa uggaguguga caaugguguu ug (SEQ ID NO: 53), pri čemu se mjesto vezanja miRNK veže na miR-122; ili
(v) mjesto vezanja miRNK sadrži nukleotidnu sekvencu koja je najmanje 80%, najmanje 85%, najmanje 90%, najmanje 95%, ili 100% identična sa caaacaccau ugucacacuc ca (SEQ ID NO: 54), pri čemu se mjesto vezanja miRNK veže na miR-122.
10. Pripravak za upotrebu prema bilo kojem prethodnom zahtjevu naznačen time što mRNK
(a) sadrži 5' neprevedenu regiju (UTR), pri čemu po izboru 5' UTR sadrži sekvencu nukleinske kiseline koja je najmanje 90%, 95%, 96%, 97%, 98%, 99%, ili 100% identična sa sekvencom navedenom u tablici 3; i/ili
(b) sadrži 3' neprevedenu regiju (UTR), pri čemu po izboru 3' UTR sadrži sekvencu nukleinske kiseline koja je najmanje 90%, 95%, 96%, 97%, 98%, 99%, ili 100% identična sa sekvencom navedenom u tablici 4A ili 4B, i/ili mRNK sadrži mjesto vezanja miRNK unutar 3' UTR, pri čemu dalje po izboru polinukleotid sadrži sekvencu nukleotidnog razmaka spojenu na mjesto vezanja miRNK pri čemu dalje po izboru sekvenca nukleotidnog razmaka sadrži najmanje 10 nukleotida, najmanje 20 nukleotida, najmanje 30 nukleotida, najmanje 40 nukleotida, najmanje 50 nukleotida, najmanje 60 nukleotida, najmanje 70 nukleotida, najmanje 80 nukleotida, najmanje 90 nukleotida, ili najmanje 100 nukleotida; i/ili
(c) sadrži strukturu 5' krajnjeg poklopca; pri čemu po izboru struktura 5' krajnjeg poklopca je Cap0, Cap1, ARCA, inozin, N1-metil-gvanozin, 2'fluoro-gvanozin, 7-deaza-gvanozin, 8-okso-gvanozin, 2-amino-gvanozin, LNA-gvanozin, 2-azidogvanozin, Cap2, Cap4, 5' metilG cap, ili njihov analog, i/ili
(d) sadrži 3' poliA rep; i/ili
(e) sadrži najmanje dva, najmanje tri, najmanje četiri, najmanje pet, najmanje šest, najmanje sedam, najmanje osam, najmanje devet ili najmanje deset mjesta vezanja miRNK; i/ili
(f) sadrži kodonom optimiziran ORF; i/ili
(g) je in vitro transkribirani (IVT) polinukleotid i/ili je kružni.
11. Pripravak za upotrebu prema bilo kojem prethodnom zahtjevu, naznačen time što lipidna nanočestica sadrži
(a) lipid odabran iz skupine koju čine DLin-DMA, DLin-K-DMA, 98N12-5, C12-200, DLin-MC3-DMA, DLin-KC2-DMA, DODMA, PLGA, PEG, PEG-DMG, PEGilirani lipidi, lipidi amino alkohola, KL22, i njihove kombinacije; ili
(b) spoj koji ima formulu (I)
[image]
ili njegova sol ili stereoizomer, pri čemu
R1 je odabran iz skupine koju čine C5-20 alkil, C5-20 alkenil, -R∗YR", -YR", i -R"M'R';
R2 i R3 su neovisno odabrani iz skupine koju čine H, C1-14 alkil, C2-14 alkenil, -R∗YR", -YR", i -R∗OR", ili R2 i R3, zajedno s atomom na koji su oni vezani, tvore heterocikl ili karbocikl;
R4 je odabran iz skupine koju čine C3-6 karbocikl, -(CH2)nQ, -(CH2)nCHQR, -CHQR, -CQ(R)2, i nesupstituirani C1-6 alkil, gdje Q je odabran od karbocikla, heterocikla, -OR, -O(CH2)nN(R)2, -C(O)OR, -OC(O)R, -CX3, -CX2H, -CXH2, -CN, -N(R)2, -C(O)N(R)2, -N(R)C(O)R, -N(R)S(O)2R, -N(R)C(O)N(R)2, -N(R)C(S)N(R)2, i -C(R)N(R)2C(O)OR, i svaki n je neovisno odabran od 1, 2, 3, 4, i 5;
svaki R5 je neovisno odabran iz skupine koju čine C1-3 alkil, C2-3 alkenil, i H;
svaki R6 je neovisno odabran iz skupine koju čine C1-3 alkil, C2-3 alkenil, i H;
M i M' su neovisno odabrani između -C(O)O-, -OC(O)-, -C(O)N(R')-, -N(R')C(O)-, -C(O)-, -C(S)-, -C(S)S-, -SC(S)-, -CH(OH)-, -P(O)(OR')O-, -S(O)2-, arilne skupine, i heteroarilne skupine;
R7 je odabran iz skupine koju čine C1-3 alkil, C2-3 alkenil, i H;
svaki R je neovisno odabran iz skupine koju čine C1-3 alkil, C2-3 alkenil, i H;
svaki R' je neovisno odabran iz skupine koju čine C1-18 alkil, C2-18 alkenil, -R∗YR", -YR", i H;
svaki R" je neovisno odabran iz skupine koju čine C3-14 alkil i C3-14 alkenil;
svaki R∗ je neovisno odabran iz skupine koju čine C1-12 alkil i C2-12 alkenil;
svaki Y je neovisno C3-6 karbocikl;
svaki X je neovisno odabran iz skupine koju čine F, Cl, Br, I; i
m je odabran od 5, 6, 7, 8, 9, 10, 11, 12, i 13; i
pod uvjetom da kada R4 je -(CH2)nQ, -(CH2)nCHQR, -CHQR, ili -CQ(R)2, tada (i) Q nije -N(R)2 kada n je 1, 2, 3, 4 ili 5, ili (ii) Q nije 5, 6, ili 7-člani heterocikloalkil kada n je 1 ili 2;
pri čemu po izboru
(i) spoj je formule (IA):
[image]
ili njegova sol ili stereoizomer, pri čemu
l je odabran od 1, 2, 3, 4, i 5;
m je odabran od 5, 6, 7, 8, i 9;
M1 je veza ili M';
R4 je nesupstituirani C1-3 alkil, ili -(CH2)nQ, gdje n je 1, 2, 3, 4, ili 5 i Q je OH, -NHC(S)N(R)2, ili -NHC(O)N(R)2;
M i M' su neovisno odabrani između -C(O)O-, -OC(O)-, -C(O)N(R')-, -P(O)(OR')O-, arilne skupine, i heteroarilne skupine; i
R2 i R3 su neovisno odabrani iz skupine koju čine H, C1-14 alkil, i C2-14 alkenil,
pri čemu poželjno m je 5, 7, ili 9; ili
(ii) spoj je formule (II):
[image]
ili njegova sol ili stereoizomer, pri čemu
l je odabran od 1, 2, 3, 4, i 5;
M1 je veza ili M';
R4 je nesupstituirani C1-3 alkil, ili -(CH2)nQ, gdje n je 2, 3, ili 4 i Q je OH, -NHC(S)N(R)2, ili -NHC(O)N(R)2;
M i M' su neovisno odabrani između -C(O)O-, -OC(O)-, -C(O)N(R')-, -P(O)(OR')O-, arilne skupine, i heteroarilne skupine; i
R2 i R3 su neovisno odabrani iz skupine koju čine H, C1-14 alkil, i
C2-14 alkenil; ili
(iii) spoj je odabran između spoja 1 do spoja 147, i njihovih soli i stereoizomera; ili
(iv) spoj je Formule (IIa),
[image]
ili njegova sol ili stereoizomer; ili
(v) spoj je Formule (IIb),
[image]
ili njegova sol ili stereoizomer; ili
(vi) spoj je Formule (IIc) ili (IIe),
[image]
[image]
ili njegova sol ili stereoizomer; ili
(vii) R4 u formuli I je odabran od -(CH2)nQ i -(CH2)nCHQR, pri čemu Q, R i n su kako je definirano gore u (b) ili (b)(i); ili
(viii) spoj je Formule (IId),
[image]
ili njegova sol ili stereoizomer,
pri čemu R2 i R3 su neovisno odabrani iz skupine koju čine C5-14 alkil i C5-14 alkenil, n je odabran od 2, 3, i 4, i R', R", R5, R6 i m su kako je definirano gore u (b) ili (b)(i), pri čemu po izboru R2 je C8 alkil, i/ili R3 je C5 alkil, C6 alkil, C7 alkil, C8 alkil, ili C9 alkil, i/ili m je 5, 7, ili 9, i/ili svaki R5 je H, pri čemu po izboru dalje svaki R6 je H.
12. Pripravak za upotrebu prema bilo kojem od prethodnih zahtjeva, naznačen time, da lipidna nanočestica sadrži spoj koji ima formulu (I)
[image]
ili njegova sol ili stereoizomer, pri čemu
R1 je odabran iz skupine koju čine C530 alkil, C520 alkenil, R∗YR", YR", i -R"M'R';
R2 i R3 su neovisno odabrani iz skupine koju čine H, C114 alkil, C2-14 alkenil, -R∗YR", YR", i R∗OR", ili R2 i R3, zajedno s atomom na koji su oni vezani, tvore heterocikl ili karbocikl;
R4 je odabran iz skupine koju čine C36 karbocikl, (CH2)nQ, - (CH2)nCHQR, -CHQR, CQ(R)2, i nesupstituirani C16 alkil, gdje Q je odabran od karbocikla, heterocikla, OR, O(CH2)nN(R)2, C(O)OR, OC(O)R, CX3, CX2H, CXH2, CN, - N(R)2, C(O)N(R)2, N(R)C(O)R, N(R)S(O)2R, N(R)C(O)N(R)2, -N(R)C(S)N(R)2, -N(R)R8, -O(CH2)nOR, -N(R)C(=NR9)N(R)2, -N(R)C(=CHR9)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -N(OR)C(O)R, -N(OR)S(O)2R, -N(OR)C(O)OR, -N(OR)C(O)N(R)2, -N(OR)C(S)N(R)2, -N(OR)C(=NR9)N(R)2, -N(OR)C(=CHR9)N(R)2, -C(=NR9)N(R)2, -C(=NR9)R, -C(O)N(R)OR, i C(R)N(R)2C(O)OR, i svaki n je neovisno odabran od 1, 2, 3, 4, i 5;
svaki R5 je neovisno odabran iz skupine koju čine C13 alkil, C23 alkenil, i H;
svaki R6 je neovisno odabran iz skupine koju čine C13 alkil, C23 alkenil, i H;
M i M' su neovisno odabrani između -C(O)O-, -OC(O)-, -C(O)N(R')-, -N(R')C(O)-, - (O)-, -C(S)-, - (S)S-, -(S)-, -CH(OH)-, -P(O)(OR')O-, -S(O)2-, -S-S- arilne skupine, i heteroarilne skupine;
R7 je odabran iz skupine koju čine C13 alkil, C23 alkenil, i H;
R8 je odabran iz skupine koju čine C3-6 karbocikl i heterocikl;
R9 je odabran iz skupine koju čine H, CN, NO2, C1-6 alkil, -OR, -S(O)2R, -S(O)2N(R)2, C2-6 alkenil, C3-6 karbocikl i heterocikl;
svaki R je neovisno odabran iz skupine koju čine C13 alkil, C23 alkenil, i H;
svaki R' je neovisno odabran iz skupine koju čine C118 alkil, C218 alkenil, -R∗YR", -", i H;
svaki R" je neovisno odabran iz skupine koju čine C314 alkil i C314 alkenil;
svaki R∗ je neovisno odabran iz skupine koju čine C112 alkil i C212 alkenil;
svaki Y je neovisno C36 karbocikl;
svaki X je neovisno odabran iz skupine koju čine F, Cl, Br, I; i m je odabran od 5, 6, 7, 8, 9, 10, 11, 12, i 13; i
pod uvjetom da kada R4 je -(CH2)nQ, -(CH2)nCHQR, -CHQR, ili -CQ(R)2, tada (i) Q nije -N(R)2 kada n je 1, 2, 3, 4 ili 5, ili (ii) Q nije 5, 6, ili 7-člani heterocikloalkil kada n je 1 ili 2; pri čemu po izboru
(a) sredstvo za isporuku sadrži spoj Formule (IA):
[image]
ili njegovu sol ili stereoizomer, pri čemu
l je odabran od 1, 2, 3, 4, i 5;
m je odabran od 5, 6, 7, 8, i 9;
M1 je veza ili M';
R4 je nesupstituirani C13 alkil, ili (CH2)nQ, u kojem Q je OH, NHC(S)N(R)2, ili -NHC(O)N(R)2, -NHC(O)N(R)2, -N(R)C(O)R, -N(R)S(O)2R, -N(R)R8, -NHC(=NR9)N(R)2, -NHC(=CHR9)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, heteroaril ili heterocikloalkil;
M i M' su neovisno odabrani između -(O)O-, -OC(O)-, -C(O)N(R')-, -P(O)(OR')O-, -S-S-, arilne skupine, i heteroarilne skupine; i
R2 i R3 su neovisno odabrani iz skupine koju čine H, C114 alkil, i C214 alkenil;
pri čemu dalje po izboru m je 5, 7, ili 9; i/ili
(b) spoj je formule (II)
[image]
ili njegova sol ili stereoizomer, pri čemu
l je odabran od 1, 2, 3, 4, i 5;
M1 je veza ili M';
R4 je nesupstituirani C13 alkil, ili (CH2)nQ, u kojem n je 2, 3, ili 4, i Q je OH, - NHC(S)N(R)2, ili NHC(O)N(R)2, -N(R)C(O)R, -N(R)S(O)2R, -N(R)R8, -NHC(=NR9)N(R)2, -NHC(=CHR9)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, heteroaril ili heterocikloalkil;
M i M' su neovisno odabrani između - (O)O-, -OC(O)-, -C(O)N(R')-, -P(O)(OR')O-, -S-S- arilne skupine, i heteroarilne skupine; i
R2 i R3 su neovisno odabrani iz skupine koju čine H, C114 alkil, i C214 alkenil; i/ili
(c) M1 je M', pri čemu po izboru M i M' su neovisno -C(O)O- ili -OC(O)-; i/ili
(d) pri čemu 1 je 1, 3, ili 5; i/ili
(e) spoj je odabran iz skupine koju čine spoj 1 do spoj 232, njihove soli i stereoizomeri, i bilo koja njihova kombinacija.
13. Pripravak za upotrebu prema bilo kojem prethodnom zahtjevu, naznačen time što
(a) fosfolipid je odabran iz skupine koju čine
1,2-dilinoleoil-sn-glicero-3-fosfokolin (DLPC),
1,2-dimiristoil-sn-glicero-fosfokolin (DMPC),
1,2-dioleoil-sn-glicero-3-fosfokolin (DOPC),
1,2-dipalmitoil-sn-glicero-3-fosfokolin (DPPC),
1,2-distearoil-sn-glicero-3-fosfokolin (DSPC),
1,2-diundekanoil-sn-glicero-fosfokolin (DUPC),
1-palmitoil-2-oleoil-sn-glicero-3-fosfokolin (POPC),
1,2-di-O-oktadecenil-sn-glicero-3-fosfokolin (18:0 Diether PC),
1-oleoil-2-kolesterilhemisukcinoil-sn-glicero-3-fosfokolin (OChemsPC),
1-heksadecil-sn-glicero-3-fosfokolin (C16 Lizo PC),
1,2-dilinolenoil-sn-glicero-3-fosfokolin,
1,2-diarahidonoil-sn-glicero-3-fosfokolin,
1,2-didokozaheksaenoil-sn-glicero-3-fosfokolin,
1,2-dioleoil-sn-glicero-3 -fosfoetanolamin (DOPE),
1,2-difitanoil-sn-glicero-3-fosfoetanolamin (ME 16:0 PE),
1,2-distearoil-sn-glicero-3-fosfoetanolamin,
1,2-dilinoleoil-sn-glicero-3 -fosfoetanolamin,
1,2-dilinolenoil-sn-glicero-3 -fosfoetanolamin,
1,2-diarahidonoil-sn-glicero-3-fosfoetanolamin,
1,2-didokozaheksaenoil-sn-glicero-3-fosfoetanolamin,
1,2-dioleoil-sn-glicero-3-fosfo-rac-(1-glicerol) natrijeva sol (DOPG), sfingomijelin,
i njihove smjese;
ili pri čemu je fosfolipid odabran iz skupine koju čine
1-miristoil-2-palmitoil-sn-glicero-3-fosfokolin (14:0-16:0 PC, MPPC),
1-miristoil-2-stearoil-sn-glicero-3-fosfokolin (14:0-18:0 PC, MSPC),
1-palmitoil-2-acetil-sn-glicero-3-fosfokolin (16:0-02:0 PC),
1-palmitoil-2-miristoil-sn-glicero-3-fosfokolin (16:0-14:0 PC, PMPC),
1-palmitoil-2-stearoil-sn-glicero-3-fosfokolin (16:0-18:0 PC, PSPC),
1-palmitoil-2-oleoil-sn-glicero-3-fosfokolin (16:0-18:1 PC, POPC),
1-palmitoil-2-linoleoil-sn-glicero-3-fosfokolin (16:0-18:2 PC, PLPC),
1-palmitoil-2-arahidonoil-sn-glicero-3-fosfokolin (16:0-20:4 PC),
1-palmitoil-2-dokozaheksaenoil-sn-glicero-3-fosfokolin (14:0-22:6 PC),
1-stearoil-2-miristoil-sn-glicero-3-fosfokolin (18:0-14:0 PC, SMPC),
1-stearoil-2-palmitoil-sn-glicero-3-fosfokolin (18:0-16:0 PC, SPPC),
1-stearoil-2-oleoil-sn-glicero-3-fosfokolin (18:0-18:1 PC, SOPC),
1-stearoil-2-linoleoil-sn-glicero-3-fosfokolin (18:0-18:2 PC),
1-stearoil-2-arahidonoil-sn-glicero-3-fosfokolin (18:0-20:4 PC),
1-stearoil-2-dokozaheksaenoil-sn-glicero-3-fosfokolin (18:0-22:6 PC),
1-oleoil-2-miristoil-sn-glicero-3-fosfokolin (18:1-14:0 PC, OMPC),
1-oleoil-2-palmitoil-sn-glicero-3-fosfokolin (18:1-16:0 PC, OPPC),
1-oleoil-2-stearoil-sn-glicero-3-fosfokolin (18:1-18:0 PC, OSPC),
1-palmitoil-2-oleoil-sn-glicero-3-fosfoetanolamin (16:0-18:1 PE, POPE),
1-palmitoil-2-linoleoil-sn-glicero-3-fosfoetanolamin (16:0-18:2 PE),
1-palmitoil-2-arahidonoil-sn-glicero-3-fosfoetanolamin (16:0-20:4 PE),
1-palmitoil-2-dokozaheksaenoil-sn-glicero-3-fosfoetanolamin (16:0-22:6 PE),
1-stearoil-2-oleoil-sn-glicero-3-fosfoetanolamin (18:0-18:1 PE),
1-stearoil-2-linoleoil-sn-glicero-3-fosfoetanolamin (18:0-18:2 PE),
1-stearoil-2-arahidonoil-sn-glicero-3-fosfoetanolamin (18:0-20:4 PE),
1-stearoil-2-dokozaheksaenoil-sn-glicero-3-fosfoetanolamin (18:0-22:6 PE),
1-oleoil-2-kolesterilhemisukcinoil-sn-glicero-3-fosfokolin (OChemsPC), i
bilo koja njihova kombinacija; i/ili
(b) sterol je odabran iz skupine koju čine kolesterol, fekosterol, sitosterol, ergosterol, kampesterol, stigmasterol, brasikasterol, tomatidin, ursolna kiselina, alfa-tokoferol, i njihove smjese; i/ili
(c) PEG lipid je odabran iz skupine koju čine PEG-modificirani fosfatidiletanolamin, PEG-modificirana fosfatidna kiselina, PEG-modificirani ceramid, PEG-modificirani dialkilamin, PEG-modificirani diacilglicerol, PEG-modificirani dialkilglicerol, i njihove smjese; i/ili
(d) lipidna nanočestica sadrži kationski lipid odabran iz skupine koju čine 3-(didodecilamino)-N1,N1,4-tridodecil-1-piperazinetanamin (KL10),
N1-[2-(didodecilamino)etil]-N1,N4,N4-tridodecil-1,4-piperazindietanamin (KL22), 14,25-ditridecil-15,18,21,24-tetraaza-oktatriakontan (KL25),
1,2-dilinoleiloksi-N,N-dimetilaminopropan (DLin-DMA),
2,2-dilinoleil-4-dimetilaminometil-[1,3]-dioksolan (DLin-K-DMA),
heptatriakonta-6,9,28,31-tetraen-19-il 4-(dimetilamino)butanoat (DLin-MC3-DMA),
2,2-dilinoleil-4-(2-dimetilaminoetil)-[1,3]-dioksolan (DLin-KC2-DMA),
1,2-dioleiloksi-N,N-dimetilaminopropan (DODMA),
2-({8-[(3β)-kolest-5-en-3-iloksi]oktil}oksi)-N,N-dimetil-3-[(9Z,12Z)-oktadeka-9,12-die-1-iloksi]propan-1-amin (Oktil-CLinDMA),
(2R)-2-({8-[(3β)-kolest-5-en-3-iloksi]oktil}oksi)-N,N-dimetil-3-[(9Z,12Z)-oktadeka-9,1 2-dien-1-iloksi]propan-1-amin (Oktil-CLinDMA (2R)), i
(2S)-2-({8-[(3β)-kolest-5-en-3-iloksi]oktil}oksi)-N,N-dimetil-3-[(9Z,12Z)-oktadeka-9,1 2-dien-1-iloksi]propan-1-amin (Oktil-CLinDMA (2S)); i/ili
(e) lipidna nanočestica sadrži kvaterni aminski spoj, pri čemu je po izboru kvaterni aminski spoj odabran iz skupine koju čine
1,2-dioleoil-3-trimetilamonij-propan (DOTAP),
N-[1-(2,3-dioleoiloksi)propil]-N,N,N-trimetilamonijev klorid (DOTMA),
1-[2-(oleoiloksi)etil]-2-oleil-3-(2-hidroksietil)imidazolinijev klorid (DOTIM),
2,3-dioleiloksi-N-[2(sperminkarboksamido)etil]-N,N-dimetil-1-propanaminij trifluoroacetat (DOSPA),
N,N-distearil-N,N-dimetilamonij bromid (DDAB),
N-(1,2-dimiristiloksiprop-3-il)-N,N-dimetil-N-hidroksietil amonij bromid (DMRIE),
N-(1,2-dioleoiloksiprop-3-il)-N,N-dimetil-N-hidroksietil amonij bromid (DORIE),
N,N-dioleil-N,N-dimetilamonij klorid (DODAC),
1,2-dilauroil-sn-glicero-3-etilfosfokolin (DLePC),
1,2-distearoil-3-trimetilamonij-propan (DSTAP),
1,2-dipalmitoil-3-trimetilamonij-propan (DPTAP),
1,2-dilinoleoil-3-trimetilamonij-propan (DLTAP),
1,2-dimiristoil-3-trimetilamonij-propan (DMTAP),
1,2-distearoil -sn-glicero-3-etilfosfokolin (DSePC),
1,2-dipalmitoil-sn-glicero-3-etilfosfokolin (DPePC),
1,2-dimiristoil-sn-glicero-3-etilfosfokolin (DMePC),
1,2-dioleoil-sn-glicero-3-etilfosfokolin (DOePC),
1,2-di-(9Z-tetradecenoil)-sn-glicero-3-etilfosfokolin (14:1 EPC),
1-palmitoil-2-oleoil-sn-glicero-3-etilfosfokolin (16:0-18:1 EPC),
i bilo koja njihova kombinacija.
14. Pripravak za upotrebu prema bilo kojem prethodnom zahtjevu, naznačen time što
(a) primjena liječi rak,
pri čemu po izboru rak je odabran iz skupine koju čine rak kore nadbubrežne žlijezde, uznapredovali rak, rak anusa, aplastična anemija, rak žučnog kanala, rak mjehura, rak kostiju, metastaza kostiju, tumor mozga, rak mozga, rak dojke, rak u djetinjstvu, rak nepoznatog primarnog podrijetla, Castlemanova bolest, rak vrata maternice, rak debelog crijeva/rektalnog karcinoma, rak endometrija, rak jednjaka, tumori iz obitelji Ewingovih tumora, rak oka, rak žučnog mjehura, gastrointestinalni karcinoidni tumori, gastrointestinalni stromalni tumori, gestacijska trofoblastična bolest, Hodgkinova bolest, Kaposijev sarkom, karcinom bubrežnih stanica, rak grkljana i hipofarinksa, akutna limfocitna leukemija, akutna mijeloična leukemija, kronična limfocitna leukemija, kronična mijeloična leukemija, kronična mijelomonocitna leukemija, rak jetre, hepatocelularni karcinom (HCC), rak pluća ne-malih stanica, rak pluća malih stanica, karcinoidni tumor pluća, limfom kože, maligni mezoteliom, multipli mijelom, mijelodisplastični sindrom, na rak nosne šupljine i paranazalnih sinusa, rak nazofarinksa, neuroblastom, ne-Hodgkinov limfom, rak usne šupljine i orofarinksa, osteosarkom, rak jajnika, rak gušterače, rak penisa, tumori hipofize, rak prostate, retinoblastom, rabdomiosarkom, rak žlijezda slinovnica, sarkom mekih tkiva kod odraslih, karcinom bazalnih i pločastih stanica kože, melanom, rak tankog crijeva, rak želuca, rak testisa, rak grla, rak timusa, rak štitnjače, sarkom maternice, rak vagine, rak vulve, Waldenstromova makroglobulinemija, Wilmsov tumor, sekundarni karcinomi uzrokovani liječenjem raka, i bilo koja njihova kombinacija; i/ili
(b) pripravak se primjenjuje pomoću uređaja koji sadrži pumpu, flaster, spremnik za lijek, uređaj s kratkom iglom, uređaj s jednom iglom, uređaj s više igala, uređaj s mikro iglama, uređaj za mlaznu injekciju, uređaj za isporuku balističkog praha/čestica, kateter, lumen, krio sondu, kanilu, mikrokanilu ili uređaje koji koriste toplinu, RF energiju, električnu struju ili bilo koju njihovu kombinaciju; i/ili
(c) učinkovita količina je između oko 0,10 mg/kg do oko 1,000 mg/kg; i/ili
(d) subjekt je čovjek.
15. Lipidna nanočestica koja sadrži mRNK koja kodira ljudski IL12 polipeptid, pri čemu mRNK sadrži ORF koji kodira ljudski IL12B polipeptid koji je operativno povezan s ljudskim IL12A polipeptidom, te lipidna nanočestica sadrži kationski lipid, fosfolipid, sterol i PEG-modificirani lipid.
16. Lipidna nanočestica prema zahtjevu 15, naznačena time što
(a) polipeptid IL12B je operativno vezan na IL12A polipeptid pomoću peptidne poveznice; i/ili
(b) polipeptid IL12B se nalazi na 5' kraju polipeptida IL12A ili peptidne poveznice; ili
(c) polipeptid IL12A se nalazi na 5' kraju polipeptida IL12B ili peptidne poveznice; i/ili
(d) peptidna poveznica sadrži Gly/Ser poveznicu, pri čemu po izboru Gly/Ser poveznica sadrži (GnS)m, pri čemu n je 1, 2 3, 4, 5, 6, 7, 8, 9, 10, 15, ili 20 i m je 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, ili 20, pri čemu dodatno po izboru Gly/Ser poveznica sadrži (GnS)m, i pri čemu n je 6 i m je 1; i/ili
(e) ORF kodira signalni peptid, pri čemu je po izboru signalni peptid ljudski IL12B signalni peptid; i/ili
(f) ljudski polipeptid IL12B sadrži aminokiselinsku sekvencu prikazanu u aminokiselinama 23 do 328 iz SEQ ID NO: 48; i/ili
(g) ljudski polipeptid IL12A sadrži aminokiselinsku sekvencu prikazanu u aminokiselinama 336 do 532 iz SEQ ID NO: 48; i/ili
(h) ljudski IL12B signalni peptid sadrži aminokiselinsku sekvencu navedenu u aminokiselinama 1 do 22 iz SEQ ID NO: 48; i/ili
(i) ljudski polipeptid IL12 sadrži sekvencu aminokiseline prikazanu u SEQ ID NO: 48; i/ili
(j) mRNK sadrži mjesto vezanja miRNK, po izboru miR-122 mjesto vezanja, dalje po izboru miR-122-3p ili miR-122-5p mjesto vezanja; dalje po izboru miR-122-5p mjesto vezanja koje sadrži sekvencu navedenu u SEQ ID NO: 54; i/ili
(k) mRNK sadrži 3' UTR, pri čemu po izboru te 3' UTR sadrži sekvencu navedenu u SEQ ID NO:240 i/ili po izboru mjesto vezanja miRNK se nalazi u 3' UTR; i/ili
(l) mRNK sadrži 5' UTR, pri čemu po izboru 5' UTR sadrži sekvencu navedenu u SEQ ID NO:39; i/ili
(m) mRNK sadrži strukturu 5' krajnjeg poklopca; pri čemu po izboru struktura 5' krajnjeg poklopca je Cap0, Cap1, ARCA, inozin, N1-metil-gvanozin, 2'fluoro-gvanozin, 7-deaza-gvanozin, 8-okso-gvanozin, 2-amino-gvanozin, LNA-gvanozin, 2-azidogvanozin, Cap2, Cap4, 5' metilG cap, ili njihov analog; i/ili
(n) mRNK sadrži 3' poliA rep; i/ili
(o) mRNK sadrži sekvencu navedenu u SEQ ID NO: 6 ili SEQ ID NO: 236 ili 237; i/ili
(p) mRNK sadrži ORF koji sadrži najmanje jedan modificirani nukleozid, pri čemu je po izboru najmanje jedan kemijski modificirani nukleozid odabran iz skupine koju čine pseudouridin, N1-metilpseudouridin, 5-metilcitozin, 5-metoksiuridin, i njihova kombinacija, pri čemu je poželjno najmanje jedan kemijski modificirani nukleozid N1-metilpseudouridin; i/ili
(q) pri čemu lipidna nanočestica sadrži od 30 mol % do 70 mol %, od 35 mol % do 65 mol %, od 40 mol % do 60 mol % ili od 45 mol % do 55 mol % spoja koji ima formulu (I):
[image]
ili njegova sol ili stereoizomer, pri čemu
R1 je odabran iz skupine koju čine C5-20 alkil, C5-20 alkenil, -R∗YR", -YR", i -R"M'R';
R2 i R3 su neovisno odabrani iz skupine koju čine H, C1-14 alkil, C2-14 alkenil, -R∗YR", -YR", i -R∗OR", ili R2 i R3, zajedno s atomom na koji su oni vezani, tvore heterocikl ili karbocikl;
R4 je odabran iz skupine koju čine C3-6 karbocikl, -(CH2)nQ, -(CH2)nCHQR, -CHQR, -CQ(R)2, i nesupstituirani C1-6 alkil, gdje je Q odabran od karbocikla, heterocikla, -OR, -O(CH2)nN(R)2, C(O)OR, OC(O)R, -CX3, -CX2H, -CXH2, -CN, -N(R)2, -C(O)N(R)2, -N(R)C(O)R, -N(R)S(O)2R, -N(R)C(O)N(R)2, -N(R)C(S)N(R)2, i -C(R)N(R)2C(O)OR, i svaki n je neovisno odabran od 1, 2, 3, 4, i 5;
svaki R5 je neovisno odabran iz skupine koju čine C1-3 alkil, C2-3 alkenil, i H;
svaki R6 je neovisno odabran iz skupine koju čine C1-3 alkil, C2-3 alkenil, i H;
M i M' su neovisno odabrani između -C(O)O-, -OC(O)-, -C(O)N(R')-, -N(R')C(O)-, -C(O)-, -C(S)-, -C(S)S-, -SC(S)-, -CH(OH)-, -P(O)(OR')O-, -S(O)2-, arilne skupine, i heteroarilne skupine;
R7 je odabran iz skupine koju čine C1-3 alkil, C2-3 alkenil, i H;
svaki R je neovisno odabran iz skupine koju čine C1-3 alkil, C2-3 alkenil, i H;
svaki R' je neovisno odabran iz skupine koju čine C1-18 alkil, C2-18 alkenil, -R∗YR", -YR", i H;
svaki R" je neovisno odabran iz skupine koju čine C3-14 alkil i C3-14 alkenil;
svaki R∗ je neovisno odabran iz skupine koju čine C1-12 alkil i C2-12 alkenil;
svaki Y je neovisno C3-6 karbocikl;
svaki X je neovisno odabran iz skupine koju čine F, Cl, Br, i I; i
m je odabran od 5, 6, 7, 8, 9, 10, 11, 12, i 13; i
pod uvjetom da kada R4 je -(CH2)nQ, -(CH2)nCHQR, -CHQR, ili -CQ(R)2, tada (i) Q nije -N(R)2 kada n je 1, 2, 3, 4 ili 5, ili (ii) Q nije 5, 6, ili 7-člani heterocikloalkil kada n je 1 ili 2; i/ili
(r) kationski lipid je spoj 18.
17. Lipidna nanočestica kako je definirana u zahtjevima 15 ili 16 za upotrebu u postupku liječenja ili odgađanja napredovanja raka kod pojedinca, naznačena time što lijek sadrži lipidnu nanočesticu i izborni farmaceutski prihvatljiv nosač, te pri čemu liječenje obuhvaća davanje lijeka u kombinaciji s pripravkom koji sadrži polipeptid inhibitora kontrolne točke i izborni farmaceutski prihvatljiv nosač.
18. Komplet koji sadrži lijek koji sadrži lipidnu nanočesticu prema zahtjevima 15 ili 16 i izborni farmaceutski prihvatljivi nosač, te uputu za pakiranje koja sadrži upute za primjenu samog lijeka ili u kombinaciji s pripravkom koji sadrži polipeptid inhibitora kontrolne točke i izborni farmaceutski prihvatljiv nosač za liječenje ili odgađanje napredovanja raka kod pojedinca, pri čemu po izboru komplet nadalje sadrži umetak u pakiranju koji sadrži upute za primjenu prvog lijeka i drugog lijeka za liječenje ili odgađanje napredovanja raka kod pojedinca.
19. Pripravak koji sadrži lipidnu nanočesticu prema zahtjevima 15 ili 16 i, izborno, farmaceutski prihvatljiv nosač, za upotrebu u liječenju ili odgađanju napredovanja raka kod pojedinca, pri čemu liječenje uključuje intratumoralno davanje navedene lipidne nanočestice u kombinaciji s drugim pripravkom, pri čemu drugi pripravak sadrži polipeptid inhibitora kontrolne točke i izborni farmaceutski prihvatljiv nosač.
20. Farmaceutski pripravak, naznačen time što sadrži nanočesticu lipida prema zahtjevima 15 ili 16 i farmaceutski prihvatljiv nosač ili pomoćnu tvar, pri čemu je izborno lipidna nanočestica formulirana za intratumoralno davanje.
21. Komplet koji sadrži spremnik koji sadrži farmaceutski pripravak prema zahtjevu 20 i uputu iz pakiranja koja sadrži upute za primjenu farmaceutskog pripravka za liječenje ili odgađanje napredovanja raka kod pojedinca, pri čemu po izboru uputa iz pakiranja dalje sadrži upute za primjenu farmaceutskog pripravka u kombinaciji s pripravkom koji sadrži polipeptid inhibitora kontrolne točke i izborni farmaceutski prihvatljiv nosač za liječenje ili odgađanje napredovanja raka kod pojedinca.
Applications Claiming Priority (4)
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