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RU2018138163A - Неоантигены и способы их использования - Google Patents

Неоантигены и способы их использования Download PDF

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Publication number
RU2018138163A
RU2018138163A RU2018138163A RU2018138163A RU2018138163A RU 2018138163 A RU2018138163 A RU 2018138163A RU 2018138163 A RU2018138163 A RU 2018138163A RU 2018138163 A RU2018138163 A RU 2018138163A RU 2018138163 A RU2018138163 A RU 2018138163A
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Prior art keywords
native polypeptide
cancer
composition
composition according
neoantigenic peptide
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RU2018138163A
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English (en)
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RU2018138163A3 (ru
RU2773273C2 (ru
Inventor
Майкл Стивен РУНИ
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Неон Терапьютикс, Инк.
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Publication of RU2018138163A publication Critical patent/RU2018138163A/ru
Publication of RU2018138163A3 publication Critical patent/RU2018138163A3/ru
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Publication of RU2773273C2 publication Critical patent/RU2773273C2/ru

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Claims (95)

1. Композиция, содержащая неоантигенный пептид или полинуклеотид, кодирующий неоантигенный пептид, где неоантигенный пептид содержит опухолеспецифичный неоэпитоп, где неоантигенный пептид не является нативным полипептидом, где неоэпитоп содержит по меньшей мере 8 смежных аминокислот аминокислотной последовательности, представленной:
AxByCz,
где
каждый из A и C представляет собой аминокислоту, соответствующую нативному полипептиду,
y представляет собой по меньшей мере 1, и B представляет собой замену или вставку аминокислоты нативного полипептида,
x+y+z составляет по меньшей мере 8,
по меньшей мере 8 смежных аминокислот содержат By, и
нативный полипептид кодируется геном, выбранным из группы, состоящей из:
(a) BRAF, где AxByCz представляет собой MIKLIDIARQTAQGMD YLHAKSIIHRDLKSNNIFLHEDLTVKIGDFGLA TEKSRWSGSHQFEQLSGSILWMAPEVIR MQDKNPYSFQSDVYAFGIVLYELM;
(b) BTK, где AxByCz представляет собой MIKEGSMSEDEFIEEAK VMMNLSHEKLVQLYG VCTKQRPIFIITEYMANGSLLNYL REMRHRFQTQQLLEMCKDVC EAMEYLESKQFLHRDLAARNCLVND;
(c) EGFR, где AxByCz представляет собой
(i) SLNITSLGLRSLKEISDG DVIISGNKNLCYANTINWKKLFG TSGQKTKIIRNRGENSCKA TGQVCHALCSPEGCWGPEPR DCVSCRNVSRGRECVDKCNLL или
(ii) IPVAIKELREATSPKANKEI LDEAYVMASVDNPHVCRLL GICLTSTVQLIMQLMPFGCLLDYVREHKDNI GSQYLLNWCVQIAKGMNYLEDRRLVHRDLAA;
(d) ESR1, где AxByCz представляет собой
(i) HLMAKAGLTLQQQHQRL AQLLLILSHIRHMSNKGMEH YSMKCKNVVPLYGLLLEM LDAHRLHAPTSRGGASVEETD QSHLATAGSTSSHSLQKYYITGEA,
(ii) NQGKCVEGMVEIFDMLLATSSRFRMMNLQGEEFVCLKSIILLNSGVYTFLPSTLKSLEEKDHIHRVLDKITDTLIHLMAKAGLTLQQQHQRLAQLLLILSH,
(iii) IHLMAKAGLTLQQQHQRLA QLLLILSHIRHMSNKGMEHLYSM KCKNVVPLCDLLLEMLDAHRLHAPTSRGGASV EETDQSHLATAGSTSSHSLQKYYITGE,
(iv) IHLMAKAGLTLQQQHQRLAQLLLILSHIRHMSNKGMEHLYSMKCKNVVPLNDLLLEMLDAHRLHAPTSRGGASVEETDQSHLATAGSTSSHSLQKYYITGE или
(v) IHLMAKAGLTLQQQHQRLAQL LLILSHIRHMSNKGMEHLYSMKCKN VVPLSDLLLEMLDAHRLHAPTSRGG ASVEETDQSHLATAGSTSSHSLQKYYITGE;
(e) PIK3CA, где AxByCz представляет собой
(i) IEEHANWSVSREAGFSYSHA GLSNRLARDNELRENDKEQL KAISTRDPLSKITEQEKDFLWSH RHYCVTIPEILPKLLLSVKWN SRDEVAQMYCLVKDWPP,
(ii) HANWSVSREAGFSYSH AGLSNRLARDNELRENDKEQLKAIST RDPLSEITKQEKDFLWSHRHYCV TIPEILPKLLLSVKWNSRDEVAQMYCLVKDWPPIKP или
(iii) LFINLFSMMLGSGMPELQ SFDDIAYIRKTLALDKTEQEALEYFMKQ MNDARHGGWTTKMDWIFHTIKQHALN;
(f) TP53, где AxByCz представляет собой
(i) IRVEGNLRVEYLDDRN TFRHSVVVPYEPPEVGSDCTTIHYNY MCNSSCMGSMNRRPILTIITL EDSSGNLLGRNSFEVRVC ACPGRDRRTEEENLRKKGEP,
(ii) TYSPALNKMFCQLAKTCPV QLWVDSTPPPGTRVRA MAIYKQSQHMTEVVRHCPHH ERCSDSDGLAPPQHLIRVEGNLR VEYLDDRNTFRHSVVVPYEPPEV,
(iii) EGNLRVEYLDDRNTFRH SVVVPYEPPEVGSDCTTIH YNYMCNSSCMGGMNQRPIL TIITLEDSSGNLLGRNSFEVRV CACPGRDRRTEEENLRKKGEPHHE,
(iv) EGNLRVEYLDDRNTFRH SVVVPYEPPEVGSDCTTIHYNYMCNSSCMGGM NWRPILTIITLEDSSGNL LGRNSFEVRVCACPGRDRR TEEENLRKKGEPHHE или
(v) PEVGSDCTTIHYNYMCNSSC MGGMNRRPILTIITLEDSSG NLLGRNSFEVCVCACPGRDRRTEEENLRKKG EPHHELPPGSTKRALPNNTSSSPQPKKKPL.
2. Композиция, содержащая неоантигенный пептид или полинуклеотид, кодирующий неоантигенный пептид, где неоантигенный пептид содержит опухолеспецифичный неоэпитоп, где неоантигенный пептид не является нативным полипептидом, где неоэпитоп содержит по меньшей мере 8 смежных аминокислот аминокислотной последовательности, представленной:
AxByCz,
где
каждый A представляет собой аминокислоту, соответствующую нативному полипептиду;
By отсутствует;
каждый C представляет собой аминокислоту, кодируемую сдвигом рамки считывания последовательности, кодирующей нативный полипептид;
x+y+z составляет по меньшей мере 8;
по меньшей мере 8 смежных аминокислот содержат по меньшей мере один Cz; и
нативный полипептид кодируется геном, выбранным из группы, состоящей из:
(a) APC, где Cz представляет собой
(i) AKFQQCHSTLEPNPAD CRVLVYLQNQPGTKLLNF LQERNLPPKVVLRHPKVHLNTMFRR PHSCLADVLLSVHLIVLRVVRLPAPFRVNHAVEW,
(ii) APVIFQIALDKPCHQAEVKHL HHLLKQLKPSEKYLKIKHLLLKRERVDLSKLQ, или
(iii) MLQFRGSRFFQMLILYYILPRKVLQMDFLVHPA;
(b) β2M, где Cz представляет собой
(i) RMERELKKWSIQTCLSARTGLSISCTTLNSPPLKKMSMPAV, или
(ii) LCSRYSLFLAWRLSSVLQRFRFTHVIQQRMESQIS;
(c) GATA3, где Cz представляет собой
(i) PGRPLQTHVLPEPHLALQPLQPH ADHAHADAPAIQPVLWTTPPLQH GHRHGLEPCSMLTGPPARVPAVPFDL HFCRSSIMKPKRDGYMFLKAESKIMFATLQRSSLWCLCSNH; или
(ii) PRPRRCTRHPACPLDHTTPPAWS PPWVRALLDAHRAPSESPCSPFRLAFLQEQYHEA; и
(d) TP53, где Cz представляет собой
(i) SSQNARGCSPRGPCTSSSYT GGPCTSPLLAPVIFCPFPENLPGQLRFPS GLLAFWDSQVCDLHVLPCPQQDVLPTGQDLPCAAVG,
(ii) GAAPTMSAAQIAMVWPLLSILS EWKEICVWSIWMTETLFDIVW WCPMSRLRLALTVPPSTTTTCVTVPAWAA,
(iii) TGGPSSPSSHWKTPVVIY WDGTALRCVFVPVLGETGAQRKRISARK GSLTTSCPQGALSEHCPTTPAPLPSQRRNHWMENISPFRSVGVSASRCSES,
(iv) FHTPARHPRPRHGHLQAVTAHDGGCEALPPP,
(v) CCPRTILNNGSLKTQVQMKLPE CQRLLPPWPLHQQLLHRRPL HQPPPGPCHLLSLPRKPTRAATVSVWASCILGQPSL,
(vi) VRKHFQTYGNYFLKTTFCPPCRPKQWMI, или
(vii) LARTPLPSTRCFANWPRPALCSCGLIPHPRPAPASAPWPSTSSHST;
(e) VHL, где Cz представляет собой
(i) ELQETGHRQVALRRSGRPPKCA ERPGAADTGAHCTSTDGRLKISV ETYTVSSQLLMVLMSLDLDTGLVPSLVSKCLILRVK,
(ii) KSDASRLSGA,
(iii) RTAYFCQYHTASVYSERAMPPGCPEPSQA,
(iv) TRASPPRSSSAIAVRASCCPYG STSTASRSPTQRCRLARAAASTAT EVTFGSSEMQGHTMGFWLTKLNYLCHLSMLTDSLFLPISHCQCIL,
(v) SSLRITGDWTSSGRSTKIWKTTQMCRKTWSG, или
(vi) RRRRGGVGRRGVRPGRVRPG GTGRRGGDGGRAAAARAALGE LARALPGHLLQSQSARRAARMAQLRRRAAALPNAAAWHGPPHPQLPRSPLALQRCRDTRWASG;
3. Композиция, содержащая неоантигенный пептид или полинуклеотид, кодирующий неоантигенный, где неоантигенный пептид содержит опухолеспецифичный неоэпитоп, где неоантигенный пептид не является нативным полипептидом, где неоэпитоп содержит по меньшей мере 8 смежных аминокислот аминокислотной последовательности, представленной:
AxByCz,
где
каждый A представляет собой аминокислоту, соответствующую первому нативному полипептиду;
каждый C представляет собой аминокислоту, соответствующую второму нативному полипептиду, или криптический экзон или экзон варианта сплайсинга первого нативного полипептида,
каждый B представляет собой аминокислоту, которая не является аминокислотой, соответствующей первому нативному полипептиду, второму нативному полипептиду или криптическому экзону первого нативного полипептида, и
x+y+z составляет по меньшей мере 8, где
y отсутствует и по меньшей мере 8 смежных аминокислот содержат по меньшей мере один Ax и по меньшей мере один Cz, или
y представляет собой по меньшей мере 1 и по меньшей мере 8 смежных аминокислот содержат по меньшей мере один By,
где:
(a) первый нативный полипептид кодируется геном BCR, второй нативный полипептид кодируется геном ABL, и
(i) y представляет собой 0, и AxByCz представляет собой ERAEWRENIREQQKKCFRSFSLTS VELQMLTNSCVKLQTVHSIPLTIN KEEALQRPVASDFEPQGLSEAA RWNSKENLLAGPSENDPNLFVALYDFVASG, или
(ii) y представляет собой 1, и AxByCz представляет собой ELQMLTNSCVKLQTVHSIPLT INKEDDESPGLYGFLNVIVHS ATGFKQSSKALQRPVASDFEPQGLSEAARWNS KENLLAGPSENDPNLFVALYDFVASGD;
(b) второй нативный полипептид кодируется ERG, y представляет собой 0, и первый нативный полипептид кодируется геном TMPRSS2, и AxByCz представляет собой MALNSEALSVVSEDQSLFECAYGTPHLAKTEMTASSSSDYGQTSKMSPRVPQQDW.
4. Композиция по любому из пп. 1-3, где неоантигенный пептид содержит последовательность в соответствии с таблицей 1.
5. Композиция по любому из пп. 1-4, где длина неоантигенного пептида составляет приблизительно от 8 приблизительно до 100 аминокислот.
6. Композиция по любому из пп. 1-5, где неоантигенный пептид связывает MHC I класса с аффинностью связывания приблизительно 500 нМ или менее.
7. Композиция по любому из пп. 1-6, где неоантигенный пептид связывает MHC II класса с аффинностью связывания 1000 нМ или менее.
8. Композиция по любому из пп. 1-7, где неоантигенный пептид дополнительно содержит фланкирующие аминокислоты, где фланкирующие аминокислоты не являются фланкирующими аминокислотами.
9. Композиция, содержащая антигенпрезентирующую клетку, содержащую композицию по любому из пп. 1-8.
10. Композиция, содержащая T-клеточный рецептор (TCR) или клетку, содержащую TCR, где TCR способен связывать комплекс MHC-пептид, содержащий по меньшей мере один неоантигенный пептид композиции по любому из пп. 1-8.
11. Композиция по любому из пп. 1-10, где композиция дополнительно содержит иммуномодулятор или адъювант.
12. Композиция по п. 11, где адъювант выбран из группы, состоящей из: поли(I:C), поли-ICLC, агониста STING, 1018 ISS, солей алюминия, Amplivax, AS15, BCG, CP-870,893, CpG7909, CyaA, dSLIM, GM-CSF, IC30, IC31, имихимода, ImuFact IMP321, IS Patch, ISS, ISCOMATRIX, JuvImmune, LipoVac, MF59, монофосфориллипида A, Montanide IMS 1312 VG, Montanide ISA 206 VG, Montanide ISA 50 V2, Montanide ISA 51 VG, OK-432, OM-174, OM-197-MP-EC, агониста ISA-TLR2, ONTAK, векторной системы PepTel®, микрочастиц PLG, резиквимода, SRL172, виросом и других вирусоподобных частиц, YF-17D, VEGF-Trap, R848, бета-глюкана, Pam3Cys, Pam3CSK4, акриловых или метакриловых полимеров, сополимеров малеинового ангидрида и стимунола QS21.
13. Композиция по любому из пп. 1-12, где композиция индуцирует CD4+T-клеточный иммунный ответ, CD8+T-клеточный иммунный ответ, гуморальный ответ или 1 тип T-хелперных клеток при введении индивидууму.
14. Композиция по любому из пп. 1-13, где композиция подходит для внутривенного, внутрибрюшинного, внутриопухолевого, внутрикожного или подкожного введения.
15. Композиция по любому из пп. 11-14, где иммуномодулятор содержит по меньшей мере один ингибитор иммунной контрольной точки.
16. Композиция по п. 15, где ингибитор иммунной контрольной точки представляет собой антитело против PD-1 или антитело против PD-L1.
17. Композиция по п. 15, где ингибитор иммунной контрольной точки выбирают из группы, состоящей из ипилимумаб, тремелимумаб, ниволумаб, авелумаб, дурвалумаб, атезолизумаб, пембролизумаб и любую их комбинацию.
18. Способ ингибирования роста опухолевой клетки, экспрессирующей опухолеспецифичный неоэпитоп, включающий приведение опухолевой клетки в контакт с композицией по любому одному из из пп. 1-17.
19. Композиция по любому из пп. 1-17 для применения при лечении злокачественной опухоли у нуждающегося в этом индивидуума, являющегося человеком.
20. Композиция по п. 19, где индивидуум проявляет тип HLA, который соответствует типу HLA в соответствии с таблицей 1 или таблицей 2.
21. Композиция по п. 19 или 20, где злокачественная опухоль выбрана из группы, состоящей из: рака мочевого пузыря, рака молочной железы, плоскоклеточного рака, колоректального рака, рака пищевода, рака желудочно-кишечного тракта, глиобластомы, рака головы и шеи, лейкоза, рака печени, рака легких, лимфомы, миеломы, рака поджелудочной железы, рака яичников, рака предстательной железы, рака почки, рака кожи, рака желудка, рака щитовидной железы и рака матки.
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