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1. WO2020234387 - IL-2/IL-15Rßy AGONIST DOSING REGIMENS FOR TREATING CANCER OR INFECTIOUS DISEASES

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[ EN ]

Cytune Pharma 20.05.2020

Claims

1. An interleukin-2/interleukin-15 receptor b g (IL-2/IL-15R b g) agonist for use in treating or managing cancer or infectious diseases, comprising administering the IL-2/IL-15R b g agonist to a human patient using a cyclical administration regimen, wherein the cyclical

administration regimen comprises:

(a) a first period of x days during which the IL-2/IL-15R b g agonist is administered at a daily dose on y consecutive days at the beginning of the first period followed by x-y days without administration of the IL-2/IL-15R b g agonist,

wherein x is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 days, preferably, 7 or 14 days, and

y is 2, 3 or 4 days, preferably 2 or 3 days;

(b) repeating the first period at least once; and

(c) a second period of z days without administration of the IL-2/IL-15R b g agonist,

wherein z is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 28, 35, 42, 49, 56, 63 or 70 days, preferably 7, 14, 21 or 56 days, more preferably 7 or 21 days.

2. The IL-2/IL-15R b g agonist for use of claim 1, comprising administering the IL-2/IL-15R b g agonist to a human patient using a cyclical administration regimen, wherein the cyclical administration regimen comprises:

(a) a first period of x days during which the IL-2/IL-15R b g agonist is administered at a daily dose on y consecutive days at the beginning of the first period followed by x-y days without administration of the IL-2/IL-15R b g agonist,

wherein x is 5, 6, 7, 8 or 9 days, preferably, 6, 7 or 8 days, more preferably 7 days, and y is 2, 3 or 4 days, preferably 2 or 3 days, more preferably 2 days;

(b) repeating the first period at least once; and

(c) a second period of z days without administration of the IL-2/IL-15R b g agonist,

wherein z is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 days, preferably 7 or 14 days, more preferably 7 days.

3. The IL-2/IL-15R b g agonist for use of any of claims 1 or 2, wherein x is 7 days, y is 2, 3 or 4 days and z is 7 days, preferably wherein y is 2 days and z is 7 days.

4. The IL-2/IL-15R b g agonist for use of any of claims 1 to 3, wherein the daily dose is 0.1 µg/kg to 50 µg/kg, preferably 0.25 µg/kg to 25µg/kg, more preferably 0.6 µg/kg to 10 µg/kg and even more preferably 2 µg/kg to 10 µg/kg.

5. The IL-2/IL-15R b g agonist for use of claim 4, wherein the daily dose is 3 µg/kg to 20 µg/kg, preferably 6 to 12 µg/kg.

6. The IL-2/IL-15R b g agonist for use of claim 4 or 5, wherein the daily dose selected within the dose range of 0.1 to 50 µg/kg is not substantially increased during the administration regimen, preferably wherein the dose is maintained during the administration regimen.

7. The IL-2/IL-15R b g agonist for use of any of claims 1 to 3, wherein the daily dose is a fixed dose independent of body weight of 7 µg to 3500 µg, preferably 17.5 µg to 1750 µg, more preferably 42 µg to 700 µg and especially 140 µg to 700 µg.

8. The IL-2/IL-15R b g agonist for use of any of claims 1 to 5 or 7, wherein the daily dose is increased during the administration regimen.

9. The IL-2/IL-15R b g agonist for use of claim 8, wherein the daily dose is increased after each period of x days.

10. The IL-2/IL-15R b g agonist for use of any of claims 8 or claim 9, wherein the daily dose is increased by 20% to 100%, preferably by 30% to 50% after each period of x days.

11. The IL-2/IL-15R b g agonist for use of claim 8, wherein the daily dose is increased once after the first period of x days.

12. The IL-2/IL-15R b g agonist for use of claim 11, wherein the daily dose is increased by 20% to 100%, preferably by 30% to 50% after the first period of x days.

13. The IL-2/IL-15R b g agonist for use of any of claims 1 to 12, wherein the daily dose is

administered in a single injection.

14. The IL-2/IL-15R b g agonist for use of any of claims 1 to 12, wherein the daily dose is split into 2 or 3 individual doses that are administered within one day, wherein the time interval between administration of the individual doses is at least about 4 h and preferably not more than 14 h.

15. The IL-2/IL-15R b g agonist for use of claim 14, wherein the daily dose is split into 3

individual doses that are administered within one day, wherein the time interval between administration of the individual doses is about 5 to about 7 h, preferably about 6 h.

16. The IL-2/IL-15R b g agonist for use of claim 14, wherein the daily dose is split into 2

individual doses that are administered within one day, wherein the time interval between administration of the individual doses is about 6 h to about 10 h, preferably about 8 h.

17. The IL-2/IL-15R b g agonist for use according to any of claims 1 to 16, wherein the IL-2/IL- 15R b g agonist is administered subcutaneously (s.c.) or intraperitoneally (i.p.), preferably s.c..

18. The IL-2/IL-15R b g agonist for use according to any of claims 1 to 17, wherein administration of the IL-2/IL-15R b g agonist in step (a) results in

(1) an increase of the % of Ki-67+ NK of total NK cells in comparison to no administration of the IL-2/IL-15R b g agonist, and wherein administration of the IL-2/IL-15R b g agonist in step (b) results in a Ki-67+ NK cell level that is at least 70% of the of the Ki-67+ NK cells of step (a), or

(2) maintenance of NK cell numbers or preferably an increase of NK cell numbers to at least 110% as compared to no administration of IL-2/IL-15R b g agonist after at least one repetition of the first period, preferably after at least two repetitions of the first period, and/or

(3) NK cell numbers of at least 1.1 x 103 NK cells/µl after at least one repetition of the first period, preferably after at least two repetitions of the first period.

19. The IL-2/IL-15R b g agonist for use according to any of claims 1 to 18, wherein the cyclic administration is repeated over at least 3 cycles, preferably 5 cycles, more preferably at least 10 cycles and even more preferably until disease progression.

20. The IL-2/IL-15R b g agonist for use according to any of claims 1 to 19, wherein the IL-2/IL- 15R b g agonist has an in vivo half-life of 30 min to 24 h, preferably 1 h to 12 h, more preferably of 2 h to 6 h.

21. The IL-2/IL-15R b g agonist for use according to any of claims 1 to 20, wherein the IL-2/IL- 15R b g agonist is an interleukin 15 (IL-15)/interleukin-15 receptor alpha (IL-15Ra) complex, preferably a fusion protein comprising the human IL-15R a sushi domain or derivative thereof, a flexible linker and the human IL-15 or derivative thereof, preferably wherein the human IL- 15R a sushi domain comprises the sequence of SEQ ID NO: 6, and wherein the human IL-15 comprises the sequence of SEQ ID NO: 4,

more preferably wherein the IL-15/IL-15R a complex is SEQ ID NO: 9.

22. The IL-2/IL-15R b g agonist for use according to any of claims 1 to 21, wherein a further

therapeutic agent is administered in combination with the IL-2/IL-15R b g agonist.

23. The IL-2/IL-15R b g agonist for use according to claim 22, wherein the further therapeutic agent and the IL-2/IL-15R b g agonist are administered on the same days and/or on different days.

24. The IL-2/IL-15R b g agonist for use according to claim 22 or claim 23, wherein administration of the further therapeutic agent occurs according to an administration regimen that is independent of the administration regimen of the IL-2/IL-15R b g agonist.

25. The IL-2/IL-15R b g agonist for use according to any of claims 22 to 24, wherein the further therapeutic agent is selected from a checkpoint inhibitor or a therapeutic antibody.

26. The IL-2/IL-15R b g agonist for use according to claim 25, wherein the checkpoint inhibitor or therapeutic antibody is administered at the beginning of the first period (a) of each cycle.

27. The IL-2/IL-15R b g agonist for use according to any of claims 25 to 26, wherein the x days and z days are adapted that

an integral multiple of x days + z days equal the days of one treatment cycle of the checkpoint inhibitor or the therapeutic antibody, or

if the treatment cycle of the checkpoint inhibitor or the therapeutic antibody changes over time, equal to each individual treatment cycle of the checkpoint inhibitor or the therapeutic antibody.

28. The IL-2/IL-15R b g agonist for use according to any of claims 25 to 27, wherein the

checkpoint inhibitor is selected from an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti- PD-L2 antibody, an anti-LAG-3 antibody, an anti-TIM-3 antibody, an anti-CTLA4 antibody or an anti-TIGIT antibody, preferably an anti-PD-L1 antibody or an anti-PD-1 antibody.

29. The IL-2/IL-15R b g agonist for use according to claim 25, wherein the therapeutic antibody is selected from an anti-CD38 antibody, an anti-CD19 antibody, an anti-CD20 antibody, an anti- CD30 antibody, an anti-CD33 antibody, an anti-CD52 antibody, an anti-CD79B antibody, an anti-EGFR antibody, an anti-HER2 antibody, an anti-VEGFR2 antibody, an anti-GD2 antibody, an anti-Nectin 4 antibody and an anti-Trop-2 antibody, preferably an anti-CD38 antibody.

30. The IL-2/IL-15R b g agonist for use according to claim 29, wherein in weeks with anti-CD38 antibody administration, the anti-CD38 antibody is administered on the 1st day or the 3rd day of the week.

31. An IL-2/IL-15R b g agonist for use in treating or managing cancer or infectious diseases, comprising administering the IL-2/IL-15R b g agonist according to the following

administration regimen

(i) administration of the IL-2/IL-15R b g agonist to a human patient at a daily dose on a first number of consecutive days; and

(ii) a second number of days without administration of the IL-2/IL-15R b g agonist, wherein the first number is 2, 3 or 4 days and the second number is 3, 4, or 5 days, wherein the first number and second add up to 7 days, preferably wherein the first number is 2 days and the second number is 5 days,

wherein the administration regimen is repeated at least once, preferably at least twice, more preferably at least 4 times, most preferably until disease progression.

32. The IL-2/IL-15R b g agonist for use of claim 31, wherein the daily dose is 0.1 to 50 µg/kg, preferably wherein the dose of 0.1 to 50 µg/kg is not substantially increased during the administration regimen, preferably wherein the dose is maintained during the administration regimen.

33. The IL-2/IL-15R b g agonist for use according to any of claims 31 to 32, wherein

administration of the IL-2/IL-15R b g agonist in step (i) results in

(1) an increase of the % of Ki-67+ NK of total NK cells in comparison to no administration of the IL-2/IL-15R b g agonist, and wherein administration of the IL-2/IL-15R b g agonist after the first repetition results in a Ki-67+ NK cell level that is at least 70% of the of the Ki-67+ NK cells of step (i),

(2) maintenance of NK cell numbers or preferably an increase of NK cell numbers to at least 110% as compared to no administration of IL-2/IL-15R b g agonist after at least one repetition of the period (i), preferably after at least two repetitions of the period (i), and/or

(3) NK cell numbers of at least 1.1 x 103 NK cells/µl after at least one repetition of the period (i), preferably after at least two repetitions of the first period.

34. The IL-2/IL-15R b g agonist for use according to any of the claims 31 to 33, wherein the IL- 2/IL-15R b g agonist has an in vivo half-life of 30 min to 24 h, preferably 1 h to 12 h, more preferably of 2 h to 6 h.

35. An IL-2/IL-15R b g agonist for use according to any of the claims 31 to 34, wherein the IL- 2/IL-15R b g agonist is an IL-15/interleukin-15 receptor alpha (IL-15Ra) complex, preferably wherein the IL-15/IL-15R a complex is a fusion protein comprising the human IL- 15R a sushi domain or derivative thereof, a flexible linker and the human IL-15 or derivative thereof, preferably wherein the human IL-15R a sushi domain comprises the sequence of SEQ ID NO: 6, and wherein the human IL-15 comprises the sequence of SEQ ID NO: 4, more preferably wherein the IL-15/IL-15R a complex is SEQ ID NO: 9.

36. The IL-2/IL-15R b g agonist for use according to any of claims 31 to 35, wherein a further therapeutic agent is administered in combination with the IL-2/IL-15R b g agonist.

37. The IL-2/IL-15R b g agonist for use according to claim 36, wherein the further therapeutic agent and the IL-2/IL-15R b g agonist are administered on the same days and/or on different days.

38. The IL-2/IL-15R b g agonist for use according to claim 36 or claim 37, wherein administration of the further therapeutic agent occurs according to an administration regimen that is independent of the administration regimen of the IL-2/IL-15R b g agonist.

39. The IL-2/IL-15R b g agonist for use according to any of claims 36 to 38, wherein the further therapeutic agent is selected from a checkpoint inhibitor or a therapeutic antibody.

40. The IL-2/IL-15R b g agonist for use according to claim 39, wherein the checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-PD-L2 antibody, an anti-LAG-3 antibody, an anti-TIM-3 antibody, an anti-CTLA4 antibody or an anti-TIGIT antibody, preferably an anti-PD-L1 antibody or an anti-PD-1 antibody.

41. The IL-2/IL-15R b g agonist for use according to claim 39, wherein the therapeutic antibody is selected from an anti-CD38 antibody, an anti-CD19 antibody, an anti-CD20 antibody, an anti- CD30 antibody, an anti-CD33 antibody, an anti-CD52 antibody, an anti-CD79B antibody, an anti-EGFR antibody, an anti-HER2 antibody, an anti-VEGFR2 antibody, an anti-GD2 antibody, an anti-Nectin 4 antibody and an anti-Trop-2 antibody, preferably an anti-CD38 antibody.