IL-2/IL-15R beta gamma agonist dosing regimens for treating cancer or infectious diseases
The present invention provides pulsed cyclic administration regimes and pulsed administration regimes for interleukin-2/interleukin-15 receptor βγ (IL-2/IL-15Rβγ) agonists for treating or managing cancer or infectious diseases in human patients. The administration regimes inter alia involve daily administration of IL-2/IL-15Rβγ agonists on 2, 3 or 4 consecutive days followed by days without administration.
1 . A method of treating or managing cancer or infectious diseases comprising administering an interleukin-2/interleukin-15 receptor βγ (IL-2/IL-15Rβγ) 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-15Rβγ 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-15Rβγ agonist, wherein x is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 days, and y is 2, 3 or 4 days;
(b) repeating the first period at least once; and
(c) a second period of z days without administration of the IL-2/IL-15Rβγ 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;
wherein the IL-2/IL-15Rβγ agonist is an interleukin 15 (IL-15)/interleukin-15 receptor alpha (IL-15Rα) complex.
2 . The method of claim 1 , wherein x is 7 days, y is 2, 3 or 4 days and z is 7 days.
3 . The method of claim 1 , wherein the daily dose is a fixed dose independent of body weight of 7 μg to 3500 μg or wherein the daily dose is 0.1 μg/kg to 50 μg/kg.
4 . The method of claim 1 , wherein the daily dose is administered in a single injection.
5 . The method of claim 1 , 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 not more than 14 h.
6 . The method of claim 1 , wherein the IL-2/IL-15Rβγ agonist is administered subcutaneously (s.c.) or intraperitoneally (i.p.).
7 . The method of claim 1 , wherein administration of the IL-2/IL-15Rβγ 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-15Rβγ agonist, and wherein administration of the IL-2/IL-15Rβγ 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),
(2) maintenance of NK cell numbers or an increase of NK cell numbers to at least 110% as compared to no administration of IL-2/IL-15Rβγ agonist after at least one repetition of the first period, after at least two repetitions of the first period, and/or
(3) NK cell numbers of at least 1.1×10 3 NK cells/ul after at least one repetition of the first period, after at least two repetitions of the first period.
8 . The method of claim 1 , wherein the interleukin 15 (IL-15)/interleukin-15 receptor alpha (IL-15Rα) complex is a fusion protein comprising the human IL-15Rα sushi domain or derivative thereof, a flexible linker and the human IL-15 or derivative thereof.
9 . The method of claim 8 , wherein the human IL-15Rα sushi domain comprises the sequence of SEQ ID NO: 6, the human IL-15 comprises the sequence of SEQ ID NO: 4, and the IL-15/IL-15Rα complex comprises the sequence of SEQ ID NO: 9.
10 . The method of claim 1 , further comprising administering a therapeutic agent in combination with the IL-2/IL-15Rβγ agonist.
11 . The method of claim 10 , wherein the therapeutic agent is a checkpoint inhibitor selected from the group consisting of 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.
12 . The method of claim 10 , wherein the therapeutic agent is a therapeutic antibody selected from the group consisting of 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.
13 . The method of claim 1 , wherein administration of the IL-15/IL-15Rα 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-15Rα agonist, and wherein administration of the IL-2/IL-15Rα 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 an increase of NK cell numbers to at least 110% as compared to no administration of IL-2/IL-15Rα agonist after at least one repetition of the period (i), after at least two repetitions of the period (i), and/or (3) NK cell numbers of at least 1.1×10 3 NK cells/ul after at least one repetition of the period (i), or after at least two repetitions of the first period.
14 . The method of claim 1 , wherein the IL-15/IL-15Rα agonist is an IL-15/interleukin-15 receptor alpha (IL-15Rα) complex, a fusion protein comprising the human IL-15Rα sushi domain or derivative thereof, a flexible linker and the human IL-15 or derivative thereof.
15 . The method of claim 14 , wherein the human IL-15Rα sushi domain comprises the sequence of SEQ ID NO: 6, the human IL-15 comprises the sequence of SEQ ID NO: 4, and the IL-15/IL-15Rα complex comprises the sequence of SEQ ID NO: 9.
16 . The method of claim 1 , further comprising administering a therapeutic agent in combination with the IL-2/IL-15Rα agonist.
17 . The method of claim 16 , wherein the therapeutic agent is a checkpoint inhibitor comprising 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.
18 . The method of claim 16 , wherein the therapeutic agent is a therapeutic antibody comprising 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.