RU2016151721A - Триспецифичные связывающие молекулы, которые специфически связывают антигены множества злокачественных опухолей, и способы их применения - Google Patents
Триспецифичные связывающие молекулы, которые специфически связывают антигены множества злокачественных опухолей, и способы их применения Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
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- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
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Claims (88)
1. Триспецифичная связывающая молекула, способная иммуноспецифично связываться с тремя различными эпитопами, причем указанные эпитопы представляют собой эпитоп I, эпитоп II и эпитоп III, где два из указанных трех эпитопов представляют собой эпитопы антигена(ов) злокачественной опухоли, а третий из указанных трех эпитопов представляет собой эпитоп антигена эффекторной клетки.
2. Триспецифичная связывающая молекула по п. 1, способная иммуноспецифично связываться с тремя различными эпитопами, где указанная связывающая молекула содержит четыре различные полипептидные цепи, ковалентно связанные вместе в виде комплекса и включает:
(i) антигенсвязывающий домен I, который способен иммуноспецифично связываться с эпитопом I, присутствующим на первом антигене, и антигенсвязывающий домен II, который способен иммуноспецифично связываться с эпитопом II, присутствующим на втором антигене, где указанный антигенсвязывающий домен I и указанный антигенсвязывающий домен II оба являются связывающими доменами типа диатела;
(ii) антигенсвязывающий домен III, который способен иммуноспецифично связываться с эпитопом III, присутствующим на третьем антигене; и
(iii) Fc-домен, который формируется за счет образования комплекса двух CH2-CH3-доменов друг с другом;
где один из эпитопа I, эпитопа II или эпитопа III представляет собой эпитоп антигена эффекторной клетки, второй из эпитопа I, эпитопа II или эпитопа III представляет собой эпитоп первого опухолевого антигена, а третий из эпитопа I, эпитопа II или эпитопа III представляет собой эпитоп второго опухолевого антигена, и где антигенсвязывающие домены I, II и III связывающих молекул опосредуют скоординированное связывание эффекторной клетки иммунной системы, экспрессирующей указанный антиген эффекторной клетки, и опухолевой клетки, экспрессирующей указанный первый и второй опухолевые антигены.
3. Триспецифичная связывающая молекула по п. 2, где указанный Fc-домен способен связываться с Fc-рецептором, развернутым на поверхности клетки.
4. Триспецифичная связывающая молекула по любому из пп. 1-3, где указанный антиген эффекторной клетки развернут на поверхности эффекторной клетки, и где указанные опухолевые антигены развернуты на поверхности опухолевой клетки, и где указанного иммуноспецифичного связывания достаточно для колокализации указанного антигена эффекторной клетки и указанных опухолевых антигенов, облегчая тем самым активацию указанной эффекторной клетки против указанной опухолевой клетки.
5. Триспецифичная связывающая молекула по любому из пп. 1-4, где антиген эффекторной клетки выбран из группы, состоящей из: CD2, CD3, CD16, CD19, CD20, CD22, CD32B, CD64, B-клеточного рецептора (BCR), Т-клеточного рецептора (TCR), и рецептора NKG2D.
6. Триспецифичная связывающая молекула по любому из пп. 1-5, где первый и второй антигены злокачественной опухоли независимо выбраны из группы, состоящей из: антигена 19,9 злокачественной опухоли ободочной кишки; муцина злокачественной опухоли желудочно-кишечного тракта; антигена 4.2; гликопротеина A33 (gpA33); ADAM-9; антигена AH6 злокачественной опухоли желудочно-кишечного тракта; ALCAM; антигена APO-1 злокачественных лимфоцитов человека; антигена В1 злокачественной опухоли; B7-H3; бета-катенина; антигена ALeb/Ley группы крови; антигена 38.13 лимфомы Беркитта, антигена C14 аденокарциномы ободочной кишки; антигена СА125 карциномы яичников; карбоксипептидазы М; CD5; CD19; CD20; CD22; CD23; CD25; CD27; CD30; CD33; CD36; CD45; CD46; CD52; CD79a/CD79b; CD103; CD317; CDK4; канцероэмбрионального антигена (СЕА); CEACAM5; CEACAM6; CO17-1A; СО-43 (антиген группы крови Le b); СО-514 (антиген группы крови Le а); СТА-1; CTLA4; цитокератина 8; антигена D1.1; антигена D1 56-22; DR5; серии E1 (группа крови B); EGFR (рецептор эпидермального фактора роста); рецептора эфрина А2 (EphA2); ErbB1; ErbB3; ErbB4; GAGE-1; GAGE-2; GD2/GD3/GM2; антигена F3 аденокарциномы легкого; антигена FC10.2; G49, ганглиозида GD2; ганглиозида GD3; ганглиозида GM2; ганглиозида GM3; GD2; GD3; GICA 19-9; GM2; gp100; Т-клеточного антигена gp37 лейкоза человека; антигена gp75 меланомы; gpA33; HER2 антигена (p185 HER2); антиген жировых глобул человеческого молока (HMFG); вирус папилломы человека-E6/вирус папилломы человека-E7; антигена меланомы высокой молекулярной массы (ВММ-MAA); I антигена (дифференцировочный антиген) I (Ma); интегрина альфа-V-бета-6; интегрина β6 (ITGB6); α2 рецептора интерлейкина-13 (IL13Rα2); JAM-3; KID3; KID31; антигена KS 1/4 пан-карциномы; антигенов L6 и L20 карциномы легкого человека; LEA; LUCA-2; М1: 22: 25: 8; M18; M39; MAGE-1; MAGE-3; MART; MUC-1; MUM-1; Myl; N-ацетилглюкозаминилтрансферазы; неогликопротеина; NS-10; OFA-1; OFA-2; онкостатина M; p15; меланома-ассоциированного антигена р97; полиморфного эпителиального муцина (PEM); антигена полиморфного эпителиального муцина (РЕМА); PIPA; простата-специфического антигена (PSA); простата-специфического мембранного антигена (PSMA); фосфатна простатической кислоты; R24; ROR1; сфинголипидов; SSEA-1; SSEA-3; SSEA-4; sTn; пептида, полученного из Т-клеточного рецептора; T5A7; TAG-72; TL5 (группа крови A); TNF-α-рецептора; TNF-β-рецептора; TNF-γ-рецептора; TRA-1-85 (группа крови Н); рецептора трансферрина; опухолеспецифичного антигена трансплантации (TSTA), кнцероэмбрионального антигена-альфа-фетопротеина (AFP); VEGF, VEGFR; VEP8; VEP9; VIM-D5; и Y гаптена, Le у.
7. Триспецифичная связывающая молекула по п. 6, где первый и второй антигены злокачественной опухоли выбирают из группы, состоящей из: CD2, CD317, CEACAM5, CEACAM6, DR5, EphA2, gpA33, Her2, В7-Н3; EGF, EGFR, VEGF и VEGFR.
8. Триспецифичная связывающая молекула по любому из пп. 1-7, где указанный связывающий домен III, не относящийся к типу диатела, содержит указанный связывающий домен Fab-типа (VLIII/VHIII), который способен иммуноспецифично связываться с эпитопом III, где указанная молекула содержит:
(А) первую полипептидную цепь, которая включает в направлении от N-конца к С-концу:
(1) вариабельный домен легкой цепи иммуноглобулина, способный связываться с первым из указанных трех эпитопов (VLI);
(2) вариабельный домен тяжелой цепи иммуноглобулина, способный связываться со вторым из указанных трех эпитопов (VHII);
(3) гетеродимер-стимулирующий домен; и
(4) домены СН2 и СН3 IgG;
(В) вторую полипептидную цепь, которая включает, в направлении от N-конца к С-концу:
(1) вариабельный домен легкой цепи иммуноглобулина, способный связываться с указанным вторым из указанных трех эпитопов (VLII);
(2) вариабельный домен тяжелой цепи иммуноглобулина, способный связываться с указанным первым из указанных трех эпитопов (VHI); и
(3) комплементарный гетеродимер-стимулирующий домен;
(С) третью полипептидную цепь, которая включает, в направлении от N-конца к С-концу:
(1) вариабельный домен тяжелой цепи иммуноглобулина, способный связываться с третьим из указанных трех эпитопов (VHIII); и
(2) домен СН1, шарнирный домен и СН2-СН3-домен IgG;
и
(D), четвертую полипептидную цепь, которая включает в направлении от N-конца к С-концу:
(1) вариабельный домен легкой цепи иммуноглобулина, способный связываться с указанным третьим из указанных трех эпитопов (VL III); и
(2) константный домен (CL) легкой цепи;
где:
(i) указанные домены VLI и VHI ассоциируют с образованием домена, способного связываться с указанным первым эпитопом;
(ii) указанные домены, VLII и VHII ассоциируют с образованием домена, способного связываться с указанным вторым эпитопом;
(iii) указанные домены VLIII и VHIII ассоциируют с образованием домена, способного связываться с указанным третьим эпитопом;
(iv) указанный CH2-CH3-домен указанной первой полипептидной цепи и указанный CH2-CH3-домен указанной третьей полипептидной цепи ассоциируют с образованием Fc-домена;
(v) указанные первая и вторая полипептидные цепи ковалентно связаны друг с другом;
(vi), указанные первая и третья полипептидные цепи ковалентно связаны друг с другом; и
(vii) указанные третья и четвертая полипептидные цепи ковалентно связаны друг с другом.
9. Триспецифичная связывающая молекула по п. 8, где:
(А) указанный гетеродимер-стимулирующий домен представляет собой E-спираль, и указанный комплементарный гетеродимер-стимулирующий домен представляет собой K-спираль; или
(B) указанный гетеродимер-стимулирующий домен представляет собой K-спираль, и указанный комплементарный гетеродимер-стимулирующий домен представляет собой E-спираль.
10. Триспецифичная связывающая молекула по любому из пп. 7-9, где:
(А) каждый из указанных доменов СН2-СН3 указанной первой и третьей полипептидных цепей имеет последовательность SEQ ID NO: 1, так что Fc-домен, образованный в результате их ассоциации демонстрирует нормальную FcγR-опосредованную эффекторную функцию; или
(В) каждый из указанных доменов СН2-СН3 указанной первой и третьей полипептидных цепей включают, по меньшей мере, одну аминокислотную замену, по отношению к последовательности SEQ ID NO: 1, так что Fc-домен, образованный в результате их ассоциации, демонстрирует измененную FcγR-опосредованную эффекторную функцию.
11. Триспецифичная связывающая молекула по п. 10, где указанная, по меньшей мере, одна аминокислотная замена включает, по меньшей мере, одну аминокислотную замену, выбранную из группы, состоящей из: L235V, F243L, R292P, Y300L, V305I и P396L, где указанная нумерация соответствует индексу EU по Kabat.
12. Триспецифичная связывающая молекула по п. 10 или 11, где указанная, по меньшей мере, одна аминокислотная замена включает:
(А), по меньшей мере, одну замену, выбранную из группы, состоящей из F243L, R292P, Y300L, V305I и P396L;
(В) по меньшей мере, две замены, выбранные из группы, состоящей из:
(1) F243L и P396L;
(2) F243L и R292P; и
(3) R292P и V305I;
(С) по меньшей мере, три замены, выбранные из группы, состоящей из:
(1) F243L, R292P и Y300L;
(2) F243L, R292P и V305I;
(3) F243L, R292P и P396L; и
(4) R292P, V305I и P396L;
(D), по меньшей мере, четыре замены, выбранные из группы, состоящей из:
(1) F243L, R292P, Y300L и P396L; и
(2) F243L, R292P, V305I и P396L;
или
(Е), по меньшей мере, пять замен, выбранных из группы, состоящей из:
(1) F243L, R292P, Y300L, V305I и P396L; и
(2) L235V, F243L, R292P, Y300L и P396L.
13. Триспецифичная связывающая молекула по любому из пп. 8-9, где указанный CH2-CH3-домен указанных первой и третьей полипептидных цепей отличаются друг от друга и содержат аминокислотную последовательность, выбранную из группы, состоящей из SEQ ID NO: 52, и SEQ ID NO: 53.
14. Триспецифичная связывающая молекула по любому из пп. 7-13, где:
(А) указанный эпитоп I, эпитоп II и эпитоп III представляет собой, соответственно, эпитоп указанного первого антигена злокачественной опухоли, эпитоп указанного второго антигена злокачественной опухоли и эпитоп указанного антигена эффекторной клетки;
(В) указанный эпитоп I, эпитоп II и эпитоп III представляет собой, соответственно, эпитоп указанного первого антигена злокачественной опухоли, эпитоп указанного антигена эффекторной клетки и эпитоп указанного второго антигена злокачественной опухоли;
(С) указанный эпитоп I, эпитоп II и эпитоп III представляет собой, соответственно, эпитоп указанного второго антигена злокачественной опухоли, эпитоп указанного первого антигена злокачественной опухоли и эпитоп указанного антигена эффекторной клетки;
(D) указанный эпитоп I, эпитоп II и эпитоп III представляет собой, соответственно, эпитоп указанного второго антигена злокачественной опухоли, эпитоп указанного антигена эффекторной клетки и эпитоп указанного первого антигена злокачественной опухоли;
(Е) указанный эпитоп I, эпитоп II и эпитоп III представляет собой, соответственно, эпитоп указанного антигена эффекторной клетки, эпитоп указанного первого антигена злокачественной опухоли, эпитоп указанного второго антигена злокачественной опухоли;
и
(F) указанный эпитоп I, эпитоп II и эпитоп III представляет собой, соответственно, эпитоп указанного антигена эффекторной клетки, эпитоп указанного второго антигена злокачественной опухоли, эпитоп указанного первого антигена злокачественной опухоли.
15. Триспецифичная связывающая молекула по любому из пп. 1-14, где:
(А) указанный эпитоп антигена эффекторной клетки представляет собой эпитоп CD2, распознаваемый антителом Lo-CD2a;
(B) указанный эпитоп антигена эффекторной клетки представляет собой эпитоп CD3, распознаваемый антителом OKT3, M291, YTH12.5, анти-CD3 моноклональным антителом 1 или анти-CD3 mAb 2;
(С) указанный эпитоп антигена эффекторной клетки представляет собой эпитоп CD16, распознаваемый антителом 3G8 или А9;
(D) указанный эпитоп антигена эффекторной клетки представляет собой эпитоп CD19, распознаваемый антителом MD1342, MEDI-551, блинатумомаб или HD37;
(Е) указанный эпитоп антигена эффекторной клетки представляет собой эпитоп CD20 эпитоп, распознаваемый антителом ритуксимаб, ибритумомаб, офатумумаб и тозитумомаб;
(F), указанный эпитоп антигена эффекторной клетки представляет собой эпитоп CD22, распознаваемый антителом эпратузумаб;
(G) указанный эпитоп антигена эффекторной клетки представляет собой эпитоп CD32B, распознаваемый антителом CD32B mAb 1;
(Н) указанный эпитоп антигена эффекторной клетки представляет собой эпитоп CD64, распознаваемый антителом CD64 mAb 1;
(I) указанный эпитоп антигена эффекторной клетки представляет собой эпитоп BCR/CD79, распознаваемый антителом CD79 mAb 1;
(J) указанный эпитоп антигена эффекторной клетки представляет собой эпитоп TCR, распознаваемый антителом BMA 031;
или
(К) указанный эпитоп антигена эффекторной клетки представляет собой эпитоп рецептора NKG2D, распознаваемый антителом KYK-2,0.
16. Фармацевтическая композиция, которая содержит триспецифичную связывающую молекулу по любому из пп. 1-15 и фармацевтически приемлемый носитель, вспомогательное вещество или разбавитель.
17. Триспецифичная связывающая молекула по любому из пп. 1-15 или фармацевтическая композиция по п. 15, где указанная молекула используется в лечении злокачественной опухоли.
18. Триспецифичная связывающая молекула по любому из пп. 1-15 или фармацевтическая композиция по п. 15, где указанная злокачественная опухоль характеризуется наличием злокачественных опухолевых клеток, выбранных из группы, состоящей из клеток: опухоли надпочечников, СПИД-ассоциированной злокачественной опухоли, альвеолярной саркомы мягких тканей, опухоли астроцитов, рака мочевого пузыря, рака кости, рака мозга и спинного мозга, метастатической опухоли мозга, рака груди, опухоли каротидной железы, рака шейки матки, хондросаркомы, хордомы, хромофобного почечно-клеточного рака, светлоклеточного рака, рака толстой кишки, колоректального рака, кожной доброкачественной фиброзной гистиоцитомы, десмопластической мелкокруглоклеточной опухоли, эпендимомы, опухоли Юинга, внескелетной миксоидной хондросаркомы, несовершенного костного фиброгенеза, фиброзной дисплазии костей, рака желчного пузыря или желчных протоков, рака желудка, гестационной трофобластической болезни, опухоли половых клеток, рака головы и шеи, гепатоцеллюлярной карциномы, опухоли островковых клеток, саркомы Капоши, рака почки, лейкоза, липомы/доброкачественной липоматозной опухоли, липосаркомы/злокачественной липоматозной опухоли, рака печени, лимфомы, рака легкого, медуллобластомы, меланомы, менингиомы, множественных эндокринных неоплазий, множественной миеломы, миелодиспластического синдрома, нейробластомы, нейроэндокринной опухоли, рака яичника, рака поджелудочной железы, папиллярного рака щитовидной железы, паратиреоидной опухоли, педиатрического рака, опухоли периферической нервной оболочки, феохромоцитомы, опухоли гипофиза, рака простаты, задней увеальной меланомы, редкого гематологического заболевания, почечного метастатического рака, палочковидной опухоли, рабдомиосаркомы, саркомы, рака кожи, саркомы мягких тканей, плоскоклеточного рака, рака желудка, синовиальной саркомы, тестикулярного рака, карциномы тимуса, тимомы, метастатического рака щитовидной железы и рака матки.
19. Триспецифичная связывающая молекула или фармацевтическая композиция по любому из пп. 17-18, где указанная злокачественная опухоль представляет собой колоректальный рак, гепатоцеллюлярный рак, глиому, рак почки, рак молочной железы, множественную миелому, рак мочевого пузыря, нейробластому; саркому, неходжкинскую лимфому, немелкоклеточный рак легкого, рак яичников, рак поджелудочной железы или рак прямой кишки.
20. Триспецифичная связывающая молекула или фармацевтическая композиция по любому из пп. 17-18, где указанная злокачественная опухоль представляет собой острый миелоидный лейкоз (AML), хронический миелолейкоз (CML), острый лимфобластный лейкоз В (B-ALL), хронический лимфоцитарный лейкоз (CLL), волосатоклеточный лейкоз (HCL), бластное неопластическое образование плазмоцитодных дендритных клеток (BPDCN), неходжкинские лимфомы (NHL), включая мантийноклеточный лейкоз (MCL), и мелкоклеточную лимфоцитарную лимфому (SLL), лимфому Ходжкина, системный мастоцитоз или лимфому Беркитта.
Applications Claiming Priority (7)
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