RU2012135395A - Антитела против рецептора фолиевой кислоты 1, их иммуноконъюгаты и использование - Google Patents

Антитела против рецептора фолиевой кислоты 1, их иммуноконъюгаты и использование Download PDF

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RU2012135395A
RU2012135395A RU2012135395/10A RU2012135395A RU2012135395A RU 2012135395 A RU2012135395 A RU 2012135395A RU 2012135395/10 A RU2012135395/10 A RU 2012135395/10A RU 2012135395 A RU2012135395 A RU 2012135395A RU 2012135395 A RU2012135395 A RU 2012135395A
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seq
heavy chain
light chain
antibody
binding fragment
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RU2012135395/10A
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RU2610663C2 (ru
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Ольга ЭБ
Дэниел ТАВАРЕС
Линюнь РУИ
Джиллиан Пэйн
Виктор С. ГОЛДМАХЕР
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Иммьюноджен, Инк.
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Abstract

1. Гуманизированное антитело или его антиген-связывающий фрагмент, специфически связывающиеся с человеческим рецептором фолиевой кислоты 1, содержащее:(а) CDR1 тяжелой цепи, содержащую GYFMN (SEQ ID NO:1); CDR2 тяжелой цепи, содержащую RIHPYDGDTFYNQXaaFXaaXaa(SEQ ID NO:56); и CDR3 тяжелой цепи, содержащую YDGSRAMDY (SEQ ID NO:3); и(б) CDR1 легкой цепи, содержащую KASQSVSFAGTSLMH (SEQ ID NO:7); CDR2 легкой цепи, содержащую RASNLEA (SEQ ID NO:8); и CDR3 легкой цепи, содержащую QQSREYPYT (SEQ ID NO:9);где Xaaвыбран из K, Q, Н и R; Хаавыбран из Q, И, N и R; и Хаавыбран из G, Е, T, S, A и V.2. Гуманизированное антитело или его антиген-связывающий фрагмент по п.1, отличающиеся тем, что последовательность CDR2 тяжелой цепи содержит RIHPYDGDTFYNQKFQG (SEQ ID NO:2).3. Гуманизированное антитело или его антиген-связывающий фрагмент по п.1 содержащие вариабельный домен тяжелой цепи, по меньшей мере приблизительно на 90%, приблизительно на 95%, приблизительно на 99%, приблизительно на 100% идентичный SEQ ID NO:4, и вариабельный домен легкой цепи, по меньшей мере приблизительно на 90%, приблизительно на 95%, приблизительно на 99%, приблизительно на 100% идентичный SEQ ID NO:10 или SEQ ID NO:11.4. Гуманизированное антитело или его антиген-связывающий фрагмент, закодированные плазмидной ДНК, депонированной в АТСС 7 апреля 2010 под номерами депонентов АТСС РТА-10772, РТА-10773 или 10774.5. Антитело или его антиген-связывающий фрагмент, которые специфически связываются с человеческим рецептором фолиевой кислоты 1, содержащее:(а) CDR1 тяжелой цепи, содержащую SSYGMS (SEQ ID NO:30); CDR2 тяжелой цепи, содержащую TISSGGSYTY (SEQ ID NO:31); и/или CDR3 тяжелой цепи, содержащую DGEGGLYAMDY (SEQ ID NO:32); иCDR1 легкой цепи, содержащую KASDHINNWLA (SEQ ID NO:27); CDR2 легкой цепи, содержащую GATSLET (SEQ ID NO:28); и CDR3 легкой цепи, содержащую QQYWSTPFT (SEQ ID NO:29);(б) CDR1 тяже�

Claims (45)

1. Гуманизированное антитело или его антиген-связывающий фрагмент, специфически связывающиеся с человеческим рецептором фолиевой кислоты 1, содержащее:
(а) CDR1 тяжелой цепи, содержащую GYFMN (SEQ ID NO:1); CDR2 тяжелой цепи, содержащую RIHPYDGDTFYNQXaa1FXaa2Xaa3 (SEQ ID NO:56); и CDR3 тяжелой цепи, содержащую YDGSRAMDY (SEQ ID NO:3); и
(б) CDR1 легкой цепи, содержащую KASQSVSFAGTSLMH (SEQ ID NO:7); CDR2 легкой цепи, содержащую RASNLEA (SEQ ID NO:8); и CDR3 легкой цепи, содержащую QQSREYPYT (SEQ ID NO:9);
где Xaa1 выбран из K, Q, Н и R; Хаа2 выбран из Q, И, N и R; и Хаа3 выбран из G, Е, T, S, A и V.
2. Гуманизированное антитело или его антиген-связывающий фрагмент по п.1, отличающиеся тем, что последовательность CDR2 тяжелой цепи содержит RIHPYDGDTFYNQKFQG (SEQ ID NO:2).
3. Гуманизированное антитело или его антиген-связывающий фрагмент по п.1 содержащие вариабельный домен тяжелой цепи, по меньшей мере приблизительно на 90%, приблизительно на 95%, приблизительно на 99%, приблизительно на 100% идентичный SEQ ID NO:4, и вариабельный домен легкой цепи, по меньшей мере приблизительно на 90%, приблизительно на 95%, приблизительно на 99%, приблизительно на 100% идентичный SEQ ID NO:10 или SEQ ID NO:11.
4. Гуманизированное антитело или его антиген-связывающий фрагмент, закодированные плазмидной ДНК, депонированной в АТСС 7 апреля 2010 под номерами депонентов АТСС РТА-10772, РТА-10773 или 10774.
5. Антитело или его антиген-связывающий фрагмент, которые специфически связываются с человеческим рецептором фолиевой кислоты 1, содержащее:
(а) CDR1 тяжелой цепи, содержащую SSYGMS (SEQ ID NO:30); CDR2 тяжелой цепи, содержащую TISSGGSYTY (SEQ ID NO:31); и/или CDR3 тяжелой цепи, содержащую DGEGGLYAMDY (SEQ ID NO:32); и
CDR1 легкой цепи, содержащую KASDHINNWLA (SEQ ID NO:27); CDR2 легкой цепи, содержащую GATSLET (SEQ ID NO:28); и CDR3 легкой цепи, содержащую QQYWSTPFT (SEQ ID NO:29);
(б) CDR1 тяжелой цепи, содержащую TNYWMQ (SEQ ID NO:60); CDR2 тяжелой цепи, содержащую AIYPGNGDSR (SEQ ID NO:61); и/или CDR3 тяжелой цепи, содержащую RDGNYAAY (SEQ ID NO:62); и
CDR1 легкой цепи, содержащую RASENIYSNLA (SEQ ID NO:57); CDR2 легкой цепи, содержащую AATNLAD (SEQ ID NO:58); и CDR3 легкой цепи, содержащую QHFWASPYT (SEQ ID NO:59);
(в) CDR1 тяжелой цепи, содержащую TNYWMY (SEQ ID NO:66); CDR2 тяжелой цепи, содержащую AIYPGNSDTT (SEQ ID NO:67); и/или CDR3 тяжелой цепи, содержащую RHDYGAMDY (SEQ ID NO:68); и
CDR1 легкой цепи, содержащую RASENIYTNLA (SEQ ID NO:63); CDR2 легкой цепи, содержащую TASNLAD (SEQ ID NO:64); и CDR3 легкой цепи, содержащую QHFWVSPYT (SEQ ID NO:65);
(г) CDR1 тяжелой цепи, содержащую SSFGMH (SEQ ID NO:72); CDR2 тяжелой цепи, содержащую YISSGSSTIS (SEQ ID NO:73); и/или CDR3 тяжелой цепи, содержащую EAYGSSMEY (SEQ ID NO:74); и
CDR1 легкой цепи, содержащую RASQNINNNLH (SEQ ID NO:69); CDR2 легкой цепи, содержащую YVSQSVS (SEQ ID NO:70); и CDR3 легкой цепи, содержащую QQSNSWPHYT (SEQ ID NO:71);
(д) CDR1 тяжелой цепи, содержащую TSYTMH (SEQ ID NO:78); CDR2 тяжелой цепи, содержащую YINPISGYTN (SEQ ID NO:79); и/или CDR3 тяжелой цепи, содержащую GGAYGRKPMDY (SEQ ID NO:80); и
CDR1 легкой цепи, содержащую KASQNVGPNVA (SEQ ID NO:75); CDR2 легкой цепи, содержащую SASYRYS (SEQ ID NO:76); и CDR3 легкой цепи, содержащую QQYNSYPYT (SEQ ID NO:77).
6. Антитело по любому из пп.1-5, отличающееся тем, что является полноразмерным антителом.
7. Антитело по любому из пп.1-5, отличающееся тем, что является антиген-связывающим фрагментом.
8. Антитело или антиген-связывающий фрагмент антитела по любому из пп.1-5, отличающееся тем, что упомянутое антитело или антиген-связывающий фрагмент содержат Fab, Fab', F(ab')2, Fd, одноцепочечный Fv или scFv, дисульфидно-связанный Fv, домен V-NAR, IgNar, интратело, IgG-CH2, минитело, F(ab')3, тетратело, триатело, диатело, однодоменное антитело, DVD-Ig, Fcab, mAb2, (scFv)2 или scFv-Fc.
9. Антитело или и его антиген-связывающий фрагмент по любому из пп.1-5, отличающиеся тем, что связываются с человеческим рецептором фолиевой кислоты 1 с Kd приблизительно 1,0 или лучше, или с Kd от приблизительно 1,0 до приблизительно 10 нМ.
10. Способ получения антитела по любому из пп.1-9, включающий (а) культивирование клетки, экспрессирующей упомянутое антитело; и (б) выделение антитела из упомянутой культивированной клетки.
11. Иммуноконъюгат с формулой (А)-(Е)-(С), в котором:
(А) является антителом или его антиген-связывающим фрагментом по любому из пп.1-9;
(L) является линкером; и
(С) является цитотоксическим агентом;
причем указанный линкер (L) соединяет (А) с (С).
12. Иммуноконъюгат по п.11, отличающийся тем, что указанный линкер выбран из группы, состоящей из расщепляемого линкера, нерасщепляемого линкера, гидрофильного линкера, линкера, основывающегося на двухосновной карбоновой кислоте.
13. Иммуноконъюгат по п.12, отличающийся тем, что упомянутый линкер выбран из группы, состоящей из: N-сукцинимидил 4-(2-пиридилдитио)пентаноата (SPP) или N-сукцинимидил 4-(2-пиридилдитио)-2-сульфопентаноата (sulfo-SPP); N-сукцинимидил 4-(2-пиридилдитио)бутаноата (SPDB) или N-сукцинимидил 4-(2-пиридилдитио)-2-сульфобутаноата (sulfo-SPDB); N-сукцинимидил 4-(малеимидометил) циклогексанкарбоксилата (SMCC); N-сульфосукцинимидил 4-(малеимидометил) циклогексанкарбоксилата (sulfoSMCC); N-сукцинимидил-4-(иодацетил)-аминобензоата (SIAB) и N-сукцинимидил-[(N-малеимидопропионамидо)-тетраэтиленгликолевого] эфира (NHS-PEG4-малеимида).
14. Иммуноконъюгат по п.12, отличающийся тем, что упомянутый линкер является N-сукцинимидил 4-(2-пиридилдитио)бутаноатом (SPDB) или N-сукцинимидил 4-(2-пиридилдитио)-2-сульфобутаноатом (sulfo-SPDB).
15. Иммуноконъюгат по любому из пп.11-14, отличающийся тем, что цитотоксический агент выбран из группы, состоящей из: майтансиниода, аналога майтансиноида, бензодиазепина, таксоида, СС-1065, аналога СС-1065, дуокармицина, аналога дуокармицина, калихеамицина, доластатина, аналога доластатина, ауристатина, производного томаимицина и производного лептомицина либо пролекарственной формы агента.
16. Иммуноконъюгат по п.15, отличающийся тем, что упомянутый цитотоксический агент является майтансиноидом.
17. Иммуноконъюгат по п.16, отличающийся тем, что упомянутый цитотоксический агент является N(2')-деацетил-N(2')-(3-меркапто-1-оксопропил)-майтансином или N(2')-деацетил-N2-(4-меркапто-4-метил-1-оксопентил)-майтансином.
18. Иммуноконъюгат, содержащий:
(А) гуманизированное антитело, содержащее вариабельный домен тяжелой цепи с последовательностями SEQ ID NO:97, 99, 101 или 103 и вариабельный домен легкой цепи с последовательностями SEQ ID NO:96, 98, 100 или 102;
(L) N-сукцинимидил 4-(малеимидометил) циклогексанкарбоксилат (SMCC); и
(С) N(2')-деацетил-N(2')-(3-меркапто-1-оксопропил)-майтансин;
причем (L) соединяет (А) с (С).
19. Иммуноконъюгат, содержащий:
(А) гуманизированное антитело, содержащее вариабельный домен тяжелой цепи с последовательностью SEQ ID NO:4 и вариабельный домен легкой цепи с последовательностью SEQ ID NO:10 или SEQ ID NO:11;
(L) N-сукцинимидил-[(N-малеимидопропионамидо)-тетраэтиленгликолевый] сложный эфир (NHS-PEG4-малеимида); N-сукцинимидил 4-(2-пиридилдитио)бутаноат (SPDB) или N-сукцинимидил 4-(2-пиридилдитио)-2-сульфобутаноат (sulfo-SPDB) и
(С)] N(2')-деацетил-N2-(4-меркапто-4-метил-1-оксопентил)-майтансин;
причем (L) соединяет (А) с (С).
20. Иммуноконъюгат, содержащий:
(А) гуманизированное антитело, содержащее вариабельный домен тяжелой цепи с последовательностью SEQ ID NO:4 и вариабельный домен легкой цепи с последовательностью SEQ ID NO:10 или SEQ ID NO:11;
(L) N-сукцинимидил 4-(2-пиридилдитио) 2-сульфопентаноат (sulfo-SPP) или N-сукцинимидил 4-(2-пиридилдитио) пентаноат (SPP); и
(С) N-(2')-деацетил-N(2')-(3-меркапто--1-оксопропил)-майтансин;
причем (L) соединяет (А) с (С).
21. Иммуноконъюгат по любому из пп.19 или 20, отличающийся тем, что указанное
гуманизированное антитело содержит вариабельный домен тяжелой цепи с последовательностью SEQ ID NO:4 и вариабельный домен легкой цепи с последовательностью SEQ ID NO:11.
22. Иммуноконъюгат по любому из пп.11-14 или 18-20, отличающийся тем, что дополнительно содержит 2-6 (С).
23. Фармацевтическая композиция, содержащая антитело по любому из пп.1-9 или Иммуноконъюгат по любому из пп.11-22, которая дополнительно содержит второй противоопухолевый агент.
24. Диагностический реактив, содержащий антитело или его антиген-связывающий фрагмент по любому из пп.1-9, которые помечены.
25. Диагностический реактив по п.24, отличающийся тем, что указанная метка выбрана из группы, состоящей из радиометки, флуорофора, хромофора, визуализирующего средства и иона металла.
26. Набор, содержащий антитело или его антиген-связывающий фрагмент по любому из пп.1-9 или иммуноконъюгат по любому из пп.11-22.
27. Способ ингибирования роста опухоли у субъекта, содержащий введение терапевтически эффективного количества антитела, антиген-связывающего фрагмента по любому из пп.1-9, иммуноконъюгата по любому из пп.11-22 или фармацевтической композиции по п.23 субъекту.
28. Способ по п.27, отличающийся тем, что рост опухоли ингибируют для лечения рака.
29. Способ лечения рака у субъекта, включающий введение терапевтически эффективного количества иммуноконъюгата с формулой (A)-(L)-(C), где:
(А) является антителом или его антиген-связывающим фрагментом по любому из пп.1-9, которые специфически связываются с человеческим рецептором фолиевой кислоты 1;
(L) является линкером; и
(С) - цитотоксин, выбранный из группы, состоящей из майтансиноида и аналога майтансиноида; причем линкер (L) соединяет (А) с (С)
30. Способ по п.29, отличающийся тем, что указанная
CDR2 тяжелой цепи содержит RIHPYDGDTFYNQKFQG (SEQ ID NO:2).
31. Способ по п.30, отличающийся тем, что указанные антитело или его антиген-связывающий фрагмент кодируются плазмидной ДНК, депонированной в АТСС 7 апреля 2010 под номерами депонентов АТСС РТА-10772, РТА-10773 или 10774.
32. Способ по п.29, отличающийся тем, что указанный иммуноконъюгат содержит:
(А) гуманизированное антитело, содержащее вариабельный домен тяжелой цепи с последовательностью SEQ ID NO:4 и вариабельный домен легкой цепи с последовательностью SEQ ID NO:10 или SEQ ID NO:11;
(L) N-сукцинимидил-[(N-малеимидопропионамидо)-тетраэтиленгликолевый] сложный эфир (NHS-PEG4-малеимид), N-сукцинимидил4-(2-пиридилдитио)бутаноат (SPDB) или N-сукцинимидил 4-(2-пиридилдитио)-2-сульфобутаноат (sulfo-SPDB); и
(С) N(2')-деацетил-N2-(4-меркапто-4-метил-1-оксопентил)-майтансин.
33. Способ по п.32, отличающийся тем, что указанное гуманизированное антитело, содержит вариабельный домен тяжелой цепи с последовательностью SEQ ID NO:4 и вариабельный домен легкой цепи с последовательностью SEQ ID NO:11.
34. Способ по п.29, отличающийся тем, что указанный иммуноконъюгат содержит
(А) гуманизированное антитело, содержащее вариабельный домен тяжелой цепи с последовательностью SEQ ID NO:4 и вариабельный домен легкой цепи с последовательностью SEQ ID NO:10 или SEQ ID NO:11;
(L) N-сукцинимидил 4-(2-пиридилдитио)-2-сульфопентаноат (sulfo-SPP) или N-сукцинимидил 4-(2-пиридилдитио)пентаноат (SPP); и
(С) N(2')-деацетил-N(2')-(3 -меркапто-1-оксопропил)-майтансин;
причем (L) соединяет (А) с (С).
35. Способ по п.29, отличающийся тем, что указанное антитело является антителом huFR-1-21, депонированным в АТСС 7 апреля 2010 под номерами депонентов АТСС РТА-10775 и РТА-10776.
36. Способ по п.29, отличающийся тем, что рост опухоли ингибируют для лечения рака.
37. Способ лечения рака у субъекта, включающий введение терапевтически эффективного количества иммуноконъюгата с формулой (A)-(L)-(C), где
(А) представляет собой антитело или антиген-связывающий фрагмент указанного антитела, которое содержит:
(а) CDR1 тяжелой цепи, содержащую SSYGMS (SEQ ID NO:30); CDR2 тяжелой цепи, содержащую TISSGGSYTY (SEQ ID NO:31); и CDR3 тяжелой цепи, содержащую DGEGGEYAMDY (SEQ ID NO:32); и
CDR1 легкой цепи, содержащую KASDHINNWLA (SEQ ID NO:27); CDR2 легкой цепи, содержащую GATSEET (SEQ ID NO:28); и CDR3 легкой цепи, содержащую QQYWSTPFT (SEQ ID NO:29);
(б) CDR1 тяжелой цепи, содержащую TNYWMQ (SEQ ID NO:60); CDR2 тяжелой цепи, содержащую AIYPGNGDSR (SEQ ID NO:61); и CDR3 тяжелой цепи, содержащую RDGNYAAY (SEQ ID NO:62); и
CDR1 легкой цепи, содержащую RASENIYSNLA (SEQ ID NO:57); CDR2 легкой цепи, содержащую AATNLAD (SEQ ID NO:58); и CDR3 легкой цепи, содержащую QHFWASPYT (SEQ ID NO:59);
(в) CDR1 тяжелой цепи, содержащую TNYWMY (SEQ ID NO:66); CDR2 тяжелой цепи, содержащую AIYPGNSDTT (SEQ ID NO:67); и CDR3 тяжелой цепи, содержащую RHDYGAMDY (SEQ ID NO:68); и
CDR1 легкой цепи, содержащую RASENIYTNLA (SEQ ID NO:63); CDR2 легкой цепи, содержащую TASNLAD (SEQ ID NO:64); и CDR3 легкой цепи, содержащую QHFWVSPYT (SEQ ID NO:65);
(г) CDR1 тяжелой цепи, содержащую SSFGMH (SEQ ID NO:72); CDR2 тяжелой цепи, содержащую YISSGSSTIS (SEQ ID NO:73); и CDR3 тяжелой цепи, содержащую EAYGSSMEY (SEQ ID NO:74); и
CDR1 легкой цепи, содержащую RASQNINNNLH (SEQ ID NO:69); CDR2 легкой цепи, содержащую YVSQSVS (SEQ ID NO:70); и CDR3 легкой цепи, содержащую QQSNSWPHYT (SEQ ID NO:71); или
(д) CDR1 тяжелой цепи, содержащую TSYTMH (SEQ ID NO:78); CDR2 тяжелой цепи, содержащую YINPISGYTN (SEQ ID NO:79); и CDR3 тяжелой цепи, содержащую GGAYGRKPMDY (SEQ ID NO:80); и
CDR1 легкой цепи, содержащую KASQNVGPNVA (SEQ ID NO:75); CDR2 легкой цепи, содержащую SASYRYS (SEQ ID NO:76); и CDR3 легкой цепи, содержащую QQYNSYPYT (SEQ ID NO:77);
(L) является линкером; и
(С) - цитотоксин, выбранный из группы, состоящей из майтансиноида и аналога майтансиноида; причем линкер (L) соединяет (А) с (С).
38. Способ по любому из пп.27-37, отличающийся тем, что опухоль является опухолью, выбранной из группы, состоящей из опухоли яичника, опухоли мозга, опухоли молочной железы, опухоли матки, опухоли эндометрия, опухоли поджелудочной железы, опухоли почки и опухоли легкого.
39. Способ по п.38, отличающийся тем, что опухоль является опухолью яичника или опухолью легкого.
40. Способ по п.37, отличающийся тем, что опухолевый рост ингибируется для лечения онкологического заболевания.
41. Способ по любому из пп.27-37, отличающийся тем, что дополнительно включает введение второго противоопухолевого препарата субъекту.
42. Способ по п.41, отличающийся тем, что указанный второй противоопухолевый агент является химиотерапевтическим агентом.
43. Изолированная клетка, продуцирующая антитело или антигенсвязывающий фрагмент по любому из пп.1-9.
44. Изолированный полинуклеотид, содержащий последовательность, по меньшей мере на 90%, по меньшей мере на 95% или по меньшей мере на 99% идентичную последовательности, выбранной из группы, состоящей из SEQ ID NOs:5, 14, 15, 37, 38, 43, 44, 47, 48 и 120-127.
45. Вектор, содержащий полинуклеотид по п.44.
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