IL-15R ALPHA FORMS, CELLS EXPRESSING IL-15R ALPHA FORMS, AND THERAPEUTIC USES OF IL-15R ALPHA AND IL-15/IL-15R ALPHA COMPLEXES
In one aspect, described herein are cyclical administration regimens for the administration of complexes comprising interleukin-15 (“IL-15”) covalently or noncovalently bound to IL-15 receptor alpha (“IL-15Ra”) to patients in order to enhance IL-15-mediated immune function. In one aspect, these cyclical administration regimens achieve plasma levels of IL-15 above basal levels while minimizing the toxicity associated with IL-15 administration. In a specific aspect, the cyclical administration regimens are useful in the prevention, treatment, and/or management of disorders in which enhancing IL-15-mediated function is beneficial, such as cancer, infectious diseases, immunodeficiencies and lymphopenia. Also described herein are purified soluble forms of IL-15Ra, cells that recombinantly express soluble forms of IL-15Ra, and compositions comprising complexes of IL-15 covalently or non-covalently bound to soluble forms of IL-15Ra. Further described herein are host cells that recombinantly express IL15-Ra derivatives comprising a mutation or deletion in the extracellular domain cleavage site, including IL-15Ra derivatives comprising the extracellular domain of IL-15Ra and a transmembrane domain of a heterologous molecule. In addition, described herein are methods for propagating, activating and/or differentiating IL-15 responsive cells, comprising co-culturing an IL-15 responsive cell(s) with a host cell(s) that recombinantly expresses IL-15Ra, and isolating the IL-15 responsive cell(s) from the host cell(s). The IL-15 responsive cells that are immune cells can be administered to prevent, treat and/or manage various disorders, including cancer, an infectious disease, an immunodeficiency and lymphopenia. Further, described herein are methods of enhancing IL-15-mediated immune function as well as methods for preventing, treating and/or managing disorders in which enhancing IL-15-mediated function is beneficial, such as cancer, in a subject, the methods comprising administering to the subject a host cell that recombinantly expresses an IL-15Ra described herein.
1 . A method for enhancing interleukin-15 (IL-15)-mediated immune function in a subject in need thereof, or treating or managing cancer in a subject in need thereof, comprising administering an IL-15/IL-15 receptor alpha (IL-15Ra) to the subject using cyclical administration regimen, wherein the cyclical administration regimen comprises: (a) administering subcutaneously to the subject a dose of 0.1 to 10 μg/kg of the IL-15/IL-15Ra complex every 1, 2 or 3 days over a first period of 1 week to 3 weeks; and (b) after a second period of 1 week to 2 months in which no IL-15/IL-15Ra complex is administered to the subject, administering subcutaneously to the subject a dose of 0.1 to 10 μg/kg of the IL-15/IL-15Ra complex every 1, 2 or 3 days over a third period of 1 week to 3 weeks.
2 . (canceled)
3 . The method claim 1 , wherein the cancer is melanoma, renal cell carcinoma, non-small cell lung cancer or colon cancer.
4 . (canceled)
5 . The method of claim 1 , wherein the dose of the IL-15/IL-15Ra complex administered over the first period and over the third period is 0.1 μg/kg, 0.25 μg/kg, 0.5 μg/kg, 1 μg/kg, 2 μg/kg or 5 μg/kg.
6 . The method of claim 1 , wherein the first period, the second period, and/or the third period is 12 to 14 days.
7 . (canceled)
8 . (canceled)
9 . The method of claim 1 , wherein the IL-15/IL-15Ra complex is a heterodimeric complex of native IL-15 and native soluble IL-15Ra.
10 . The method of claim 1 , wherein the IL-15 is human IL-15, and wherein IL-15Ra is a soluble form of human IL-15Ra.
11 . The method of claim 9 , wherein the native IL-15 is human IL-15 and the native soluble IL-15Ra is soluble human IL-15a.
12 . The method of claim 1 , wherein:
(a) human IL-15 comprises amino acid residues 49 to 162 of the amino acid sequence of SEQ ID NO: 1; and
(b) human IL-15Ra comprises the amino acid sequence of SEQ ID NO: 33, 35, 37, 39, 41 or 45.
13 . The method of claim 11 , wherein:
(a) human IL-15 comprises amino acid residues 49 to 162 of the amino acid sequence of SEQ ID NO: 1; and
(b) human IL-15Ra comprises the amino acid sequence of SEQ ID NO: 33.
14 . (canceled)
15 . The method of claim 10 , wherein the human IL-15Ra is glycosylated such that glycosylation accounts for at least 20%, 30%, 40% or 50% of the mass of the human IL-15Ra.
16 . The method of claim 15 , wherein the IL-15Ra is:
a. O-glycosylated on Thr5 of amino acid sequence NWELTASASHQPPGVYPQG (SEQ ID NO: 42) in the IL-15Ra;
b. O-glycosylated on Ser7 of amino acid sequence NWELTASASHQPPGVYPQG (SEQ ID NO: 42) in the IL-15Ra;
c. N-glycosylated on Ser 8 of amino acid sequence ITCPPPMSVEHADIWVK (SEQ ID NO: 43) in the IL-15Ra;
d. N-glycosylated on Ser 8 of amino acid sequence ITCPPPMSVEHADIWVKSYSLYSRERYICNS (SEQ ID NO: 44) in the IL-15Ra;
e. N-glycosylated on Ser 18 of amino acid sequence ITCPPPMSVEHADIWVKSYSLYSRERYICNS (SEQ ID NO: 44) in the IL-15Ra;
f. N-glycosylated on Ser 20 of amino acid sequence ITCPPPMSVEHADIWVKSYSLYSRERYICNS (SEQ ID NO: 44) in the IL-15Ra;
g. N-glycosylated on Ser 23 of amino acid sequence ITCPPPMSVEHADIWVKSYSLYSRERYICNS (SEQ ID NO: 44) in the IL-15Ra; and/or
h. N-glycosylated on Ser 31 of amino acid sequence ITCPPPMSVEHADIWVKSYSLYSRERYICNS (SEQ ID NO: 44) in the IL-15Ra.
17 . (canceled)
18 . The method of claim 1 , wherein the subject is human.
19 . A purified soluble form of human IL-15Ra, wherein:
a. the last amino acids at the C-terminal end of the soluble form of human IL-15Ra consist of amino acid residues PQGHSDTT (SEQ ID NO: 26), wherein T is at the C-terminal end of the amino acid sequence;
b. the last amino acids at the C-terminal end of the soluble form of human IL-15Ra consist of amino acid residues PQGHSDT (SEQ ID NO: 27), wherein T is at the C-terminal end of the amino acid sequence;
c. the last amino acids at the C-terminal end of the soluble form of human IL-15Ra consist of amino acid residues PQGHSD (SEQ ID NO: 28), wherein D is at the C-terminal end of the amino acid sequence;
d. the last amino acids at the C-terminal end of the soluble form of IL-15Ra consist of amino acid residues PQGHS (SEQ ID NO: 29), wherein S is at the C-terminal end of the amino acid sequence;
e. the last amino acids at the C-terminal end of the soluble form of human IL-15Ra consist of amino acid residues PQGH (SEQ ID NO: 30), wherein H is at the C-terminal end of the amino acid sequence; or
f. the last amino acids at the C-terminal end of the soluble form of human IL-15Ra consist of amino acid residues PQG (SEQ ID NO: 31), wherein G is at the C-terminal end of the amino acid sequence.
20 . The purified soluble form of claim 19 , wherein the soluble form of human IL-15Ra is glycosylated such that glycosylation accounts for at least or more than 20%, 30%, 40% or 50% of the mass of the IL-15Ra.
21 . (canceled)
22 . A purified soluble form of IL-15Ra which is glycosylated such that glycosylation accounts for at least or more than 20%, 30%, 40% or 50% of the mass of the IL-15Ra.
23 . The purified soluble form of claim 22 , wherein the soluble form of IL-15Ra is a soluble form of human IL-15Ra.
24 . (canceled)
25 . (canceled)
26 . A purified soluble form of human IL-15Ra comprising the amino acid sequence of SEQ ID NO: 33, 35, 37, 39, 41 or 45.
27 . An IL-15Ra derivative comprising;
(a) the amino acid sequence of the extracellular domain of human IL-15Ra with one, two, three, four, five, six, seven, or eight amino acid substitutions and/or deletions in the amino acid sequence PQGHSDTT (SEQ ID NO: 26) of human IL-15Ra such that cleavage by an endogenous protease that cleaves human IL-15Ra is inhibited; or
(b) (i) the extracellular domain of human IL-15Ra with one, two, three, four, five, six, seven or eight substitutions and/or deletions in the amino acid sequence PQGHSDTT (SEQ ID NO:26) such that cleavage by an endogenous protease that cleaves human IL-15Ra is inhibited, and (ii) a transmembrane domain of a heterologous molecule in place of the transmembrane domain of human IL-15Ra.
28 . (canceled)
29 . (canceled)
30 . A composition comprising a complex of the soluble form of IL-15Ra of claim 19 with IL-15.
31 . (canceled)
32 . (canceled)
33 . (canceled)
34 . A host cell that recombinantly expresses a soluble form of human IL-15Ra of claim 19 .
35 . (canceled)
36 . (canceled)
37 . A host cell that recombinantly expresses a soluble form of IL-15Ra of claim 26 .
38 . A host cell that recombinantly expresses an IL-15Ra derivative of claim 27 .
39 . (canceled)
40 . (canceled)
41 . The host cell of claim 34 , which further recombinantly expresses IL-15.
42 . (canceled)
43 . A method for propagating, activating and/or differentiating an IL-15-responsive immune cell, comprising co-culturing the host cell of claim 34 with the IL-15-responsive immune cell in the presence of IL-15 for a period of time, and isolating the IL-15Ra-responsive immune cell from the host cell.
44 . A method for propagating, activating and/or differentiating an IL-15-responsive immune cell, comprising co-culturing the host cell of claim 41 with the IL-15-responsive immune cell for a period of time, and isolating the IL-15Ra-responsive immune cell from the host cell.
45 . (canceled)
46 . A method for enhancing IL-15-mediated immune function in a subject in need thereof or treating or managing cancer in a subject in need thereof comprising administering the host cell of claim 34 to the subject.
47 . (canceled)
48 . (canceled)
49 . (canceled)
50 . (canceled)
51 . (canceled)
52 . (canceled)
53 . (canceled)
54 . (canceled)
55 . (canceled)
56 . The method of claim 1 which further comprises administering another therapy.
57 . The method of 56 , wherein the other therapy is an antibody that immunospecifically binds to PD-1, an antibody that immunospecifically binds to PD-L1, or an antibody that immunospecifically binds to Her-2.
58 . (canceled)