METHODS AND COMPOSITIONS FOR TREATING MYELOFIBROSIS
In part, the present disclosure relates methods for treating, preventing, or reducing the progression rate and/or severity of myelofibrosis or one or more complications of myelofibrosis (extramedullary hematopoiesis, splenomegaly, anemia, and fibrosis). In certain aspects, the disclosure provides ActRIIB antagonists for use in treating, preventing, or reducing the progression rate and/or severity of one or more complications associated with Janus kinase inhibitor therapy in a patient (e.g., anemia).
1 - 2 . (canceled)
3 . A method for treating myelofibrosis, comprising administering to a patient in need thereof: a) a Janus kinase inhibitor; and b) an ActRIIB polypeptide, wherein the Janus kinase inhibitor and ActRIIB polypeptide are administered in an effective amount, and wherein the ActRIIB polypeptide comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a sequence starting at a residue corresponding to any one of amino acids 20-29 of SEQ ID NO: 1 and ending at a residue corresponding to any one of amino acids 109-134 of SEQ ID NO: 1.
4 . (canceled)
5 . The method of claim 3 , wherein the method decreases one or more of: bone marrow fibrosis, spleen fibrosis, liver fibrosis, lung fibrosis, and lymph node fibrosis.
6 - 11 . (canceled)
12 . The method of claim 3 , wherein the method increases red blood cell levels in the patient.
13 . The method of claim 3 , wherein the method increases hemoglobin levels in the patient.
14 . The method of claim 3 , wherein the patient has anemia.
15 . The method of claim 14 , wherein the method treats the anemia.
16 . The method of claim 3 , wherein the patient has been administered one or more blood cell transfusions prior to the start of ActRIIB polypeptide treatment.
17 . The method of claim 3 , wherein the patient is blood cell transfusion-dependent.
18 . The method of claim 17 , wherein the method decreases blood cell transfusion burden.
19 . The method of claim 18 , wherein the method decreases blood cell transfusion by greater than about 30% for 4 to 8 weeks relative to the equal time prior to the start of the ActRIIB polypeptide treatment.
20 - 22 . (canceled)
23 . The method of claim 3 wherein the patient has primary myelofibrosis.
24 . The method of claim 3 wherein the patient has post-polycythemia vera myelofibrosis.
25 . The method of claim 3 wherein the patient has post-essential thrombocythemia myelofibrosis.
26 - 31 . (canceled)
32 . The method of claim 3 , wherein the myelofibrosis is associated with one or more mutations in JAK2.
33 . The method of claim 32 , wherein the JAK2 mutation is JAK2V617F.
34 . (canceled)
35 . The method of claim 3 , wherein the patient has been treated with a Janus kinase inhibitor.
36 . The method of claim 3 , wherein the patient is intolerant of or has an inadequate response to a Janus kinase inhibitor.
37 - 42 . (canceled)
43 . The method of claim 36 , wherein the Janus kinase inhibitor is selected from the group consisting of: ruxolitinib, fedratinib (SAR302503), monoelotinib (CYT387), pacritinib, lestaurtinib, AZD-1480, BMS-911543, NS-018, LY2784544, SEP-701, XL019, and AT-9283.
44 . The method of claim 43 , wherein the Janus kinase inhibitor is ruxolitinib.
45 - 46 . (canceled)
47 . The method of claim 3 , wherein the patient is further administered hydroxyurea or has previously been treated with hydroxyurea.
48 . The method of claim 3 , wherein the patient is intolerant of hydroxyurea or has an inadequate response to hydroxyurea.
49 . A method for increasing red blood cell levels and/or hemoglobin levels in a patient treated with a Janus kinase inhibitor, comprising administering to a patient in need thereof an effective amount of an ActRIIB polypeptide, wherein the ActRIIB polypeptide comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a sequence starting at a residue corresponding to any one of amino acids 20-29 of SEQ ID NO: 1 and ending at a residue corresponding to any one of amino acids 109-134 of SEQ ID NO: 1.
50 . The method of claim 49 , wherein the patient has anemia.
51 . The method of claim 50 , wherein the method treats the anemia.
52 - 53 . (canceled)
54 . The method of claim 49 , wherein the patient has been administered one or more blood cell transfusions prior to the start of ActRIIB polypeptide treatment.
55 . The method of claim 49 , wherein the patient is blood cell transfusion-dependent.
56 . The method of claim 55 , wherein the method decreases blood cell transfusion burden.
57 . The method of claim 56 , wherein the method decreases blood cell transfusion by greater than about 30% for 4 to 8 weeks relative to the equal time prior to the start of the ActRIIB polypeptide treatment.
58 - 65 . (canceled)
66 . The method of claim 49 , wherein the Janus kinase inhibitor is selected from the group consisting of: ruxolitinib, fedratinib (SAR302503), monoelotinib (CYT387), pacritinib, lestaurtinib, AZD-1480, BMS-911543, NS-018, LY2784544, SEP-701, XL019, and AT-9283.
67 . The method of claim 66 , wherein the Janus kinase inhibitor is ruxolitinib.
68 . (canceled)
69 . The method of claim 3 , wherein the ActRIIB polypeptide is selected from the group consisting of:
a) a polypeptide comprising an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to amino acids 29-109 of SEQ ID NO: 1;
b) a polypeptide comprising an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to amino acids 25-131 of SEQ ID NO: 1;
c) a polypeptide comprising an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 2;
d) a polypeptide comprising an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 3;
e) a polypeptide comprising an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 4;
f) a polypeptide comprising an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5;
g) a polypeptide comprising an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 6;
h) a polypeptide comprising an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 30; and
i) a polypeptide comprising an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 54.
70 . The method of claim 69 , wherein the polypeptide comprises an acidic amino acid at the amino acid position corresponding to position 79 of SEQ ID NO: 1.
71 . The method of claim 70 , wherein the polypeptide comprises a D at the amino acid position corresponding to position 79 of SEQ ID NO: 1.
72 . The method of claim 70 , wherein the polypeptide comprises a E at the amino acid position corresponding to position 79 of SEQ ID NO: 1.
73 . The method of claim 69 , wherein the polypeptide is a fusion protein comprising an immunoglobulin Fc domain.
74 . The method of claim 73 , wherein the immunoglobulin Fc domain is from an IgG1 Fc domain.
75 . (canceled)
76 . The method of claim 73 , wherein the fusion protein further comprises a linker domain positioned between the ActRIIB domain and the immunoglobulin Fc domain.
77 . (canceled)
78 . A method for treating myelofibrosis, comprising administering to a patient in need thereof: a Janus kinase inhibitor; and b) an ActRIIB polypeptide, wherein the Janus kinase inhibitor are administered in an effective amount, and wherein the polypeptide is an ActRIIB-Fc fusion protein comprising a polypeptide selected from:
a) a polypeptide comprising an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 24;
b) a polypeptide comprising an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 25;
c) a polypeptide comprising an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 28;
d) a polypeptide comprising an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 29;
e) a polypeptide comprising an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 31;
f) a polypeptide comprising an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 45;
g) a polypeptide comprising an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 50;
h) a polypeptide comprising an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 53; and
i) a polypeptide comprising an amino acid sequence that is at least 70%, 75% 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 58.
79 - 91 . (canceled)
92 . A method of for treating myelofibrosis, comprising administering to a patient in need thereof: a Janus kinase inhibitor; and b) an ActRIIB antagonist, wherein the Janus kinase inhibitor are administered in an effective amount, and wherein the ActRIIB antagonist is:
i. an antibody or combination of antibodies
ii. a follistatin polypeptide
iii. a FLRG polypeptide.
93 - 114 . (canceled)
115 . The method of claim 3 , wherein the ActRIIB polypeptide comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 53.
116 . The method of claim 3 , wherein the ActRIIB polypeptide comprises the amino acid sequence of SEQ ID NO: 53.