Treatment of congestive heart failure and other cardiac dysfunction using a GDF15 modulator
The invention provides methods and compositions of treating a subject having a cardiac-related disorder such as congestive or chronic heart failure (CHF), cardiac hypertrophy, cardiac hypotrophy, and other cardiac myopathies/dystrophies. The methods comprise administering an effective amount of a composition that modulates, for example, reduces or inhibits, GDF15 activity in the subject.
1 . A method of treating cardiac hypotrophy in a subject in need thereof, the method comprising administering to the subject an effective amount of an anti-GDF15 antibody selected from the group consisting of
a) an antibody comprising the heavy chain sequence of SEQ ID NO:47 or 49 and the light chain sequence of SEQ ID NO:30;
b) an antibody comprising the heavy chain sequence of SEQ ID NO:41, 42, 43, 44, 45, 46, 48, or 49 and the light chain sequence of SEQ ID NO:29;
c) an antibody comprising the heavy chain sequence of SEQ ID NO:41, 42, 43, 44, or 45 and the light chain sequence of SEQ ID NO:28;
d) an antibody comprising the heavy chain sequence of SEQ ID NO:39, 40, 41, 42, 43, 44, or 45 and the light chain sequence of SEQ ID NO:27;
e) an antibody comprising the heavy chain sequence of SEQ ID NO:38 and the light chain sequence of SEQ ID NO:26;
f) an antibody comprising the heavy chain sequence of SEQ ID NO:37 and the light chain sequence of SEQ ID NO:25;
g) an antibody comprising a heavy chain CDR H1 sequence of SEQ ID NO:1, a heavy chain CDR H2 sequence of SEQ ID NO:7, and a heavy chain CDR H3 sequence of SEQ ID NO:13; and
a light chain CDR L1 sequence of SEQ ID NO:16, a light chain CDR L2 sequence of SEQ ID NO:18, and a light chain CDR L3 sequence of SEQ ID NO:22;
h) an antibody comprising a heavy chain CDR H1 sequence of SEQ ID NO:1, a heavy chain CDR H2 sequence of SEQ ID NO:9, and a heavy chain CDR H3 sequence of SEQ ID NO:13; and
a light chain CDR L1 sequence of SEQ ID NO:16, a light chain CDR L2 sequence of SEQ ID NO:18, and a light chain CDR L3 sequence of SEQ ID NO:22;
i) an antibody comprising a heavy chain CDR H1 sequence of SEQ ID NO:1, a heavy chain CDR H2 sequence of SEQ ID NO:4, and a heavy chain CDR H3 sequence of SEQ ID NO:13; and
a light chain CDR L1 sequence of SEQ ID NO:16, a light chain CDR L2 sequence of SEQ ID NO:18, and a light chain CDR L3 sequence of SEQ ID NO:21;
j) an antibody comprising a heavy chain CDR H1 sequence of SEQ ID NO:1, a heavy chain CDR H2 sequence of SEQ ID NO:5, and a heavy chain CDR H3 sequence of SEQ ID NO:13; and
a light chain CDR L1 sequence of SEQ ID NO:16, a light chain CDR L2 sequence of SEQ ID NO:18, and a light chain CDR L3 sequence of SEQ ID NO:21;
k) an antibody comprising a heavy chain CDR H1 sequence of SEQ ID NO:1, a heavy chain CDR H2 sequence of SEQ ID NO:6, and a heavy chain CDR H3 sequence of SEQ ID NO:13; and
a light chain CDR L1 sequence of SEQ ID NO:16, a light chain CDR L2 sequence of SEQ ID NO:18, and a light chain CDR L3 sequence of SEQ ID NO:21;
l. an antibody comprising a heavy chain CDR H1 sequence of SEQ ID NO:1, a heavy chain CDR H2 sequence of SEQ ID NO:8, and a heavy chain CDR H3 sequence of SEQ ID NO:13; and
a light chain CDR L1 sequence of SEQ ID NO:16, a light chain CDR L2 sequence of SEQ ID NO:18, and a light chain CDR L3 sequence of SEQ ID NO:21; and
m) an antibody comprising a heavy chain CDR H1 sequence of SEQ ID NO:1, a heavy chain CDR H2 sequence of SEQ ID NO:9, and a heavy chain CDR H3 sequence of SEQ ID NO:13; and
a light chain CDR L1 sequence of SEQ ID NO:16, a light chain CDR L2 sequence of SEQ ID NO:18, and a light chain CDR L3 sequence of SEQ ID NO:21,
thereby reducing or inhibiting GDF15 activity in the subject.
2 . The method of claim 1 , wherein the antibody is humanized or human.
3 . The method of claim 1 , wherein the anti-GDF15 antibody comprises the heavy chain sequence of SEQ ID NO:47 and the light chain sequence of SEQ ID NO:30.
4 . The method of claim 1 , wherein the anti-GDF15 antibody comprises a heavy chain CDR H1 sequence of SEQ ID NO:1, a heavy chain CDR H2 sequence of SEQ ID NO:7, and a heavy chain CDR H3 sequence of SEQ ID NO:13; and a light chain CDR L1 sequence of SEQ ID NO:16, a light chain CDR L2 sequence of SEQ ID NO:18, and a light chain CDR L3 sequence of SEQ ID NO:22.
5 . The method of claim 1 , wherein the anti-GDF15 antibody comprises the heavy chain sequence of SEQ ID NO:48 and the light chain sequence of SEQ ID NO:29.
6 . The method of claim 1 , wherein the anti-GDF15 antibody comprises a heavy chain CDR H1 sequence of SEQ ID NO:1, a heavy chain CDR H2 sequence of SEQ ID NO:8, and a heavy chain CDR H3 sequence of SEQ ID NO:13; and a light chain CDR L1 sequence of SEQ ID NO:16, a light chain CDR L2 sequence of SEQ ID NO:18, and a light chain CDR L3 sequence of SEQ ID NO:21.