Modified therapeutic agents and compositions thereof
Methods and compositions are provided for extending the half-life of a therapeutic agent. One or more half-life extending moieties may be attached to a therapeutic agent, thereby extending the half life of the therapeutic agent. The modified therapeutic agents (mTAs) comprising one or more half-life extending moieties attached to a therapeutic agent may be used to treat a disease or condition in a subject in need thereof.
1. A lipid conjugate (LC), comprising
a. one or more lipids, the lipids selected from a group consisting of sterols, bile acids, vitamin E, fatty di-acids, fatty acids, fatty amides, fatty amines, fatty alcohols, and derivatives thereof; and
b. a therapeutic agent (TA) comprising an amino acid sequence that is SEQ ID NO: 45;
wherein the one or more lipids are conjugated to the TA via a cysteine residue at the N-terminus of SEQ ID NO: 45.
2. The LC of claim 1 , wherein the LC has the structure:
TA-A 1 -P 1 -L Formula (I)
wherein:
TA is the therapeutic agent;
A 1 is a chemical group linking TA and P 1 or L;
P 1 is a bond or comprises polyglycol; and
L is the lipid.
3. The LC of claim 2 , wherein a sulfur atom of the cysteine residue of the TA is connected to A 1 via a chemical bond.
4. The LC of claim 2 , wherein
A 1 is selected from
P 1 is -PEG-A 2 -;
PEG is selected from
A 2 is selected from a bond,
L is tetradecanoic acid, octadecanedioic acid, tetradecylamine, myristic acid, stearic acid, docosahexaenoic acid, lithocholic acid ester, cholic acid or palmitic acid;
X is a bond, NR 5 , S, or O;
each R 1 , R 2 , R 3 , and R 4 is independently selected from H, halo, CN, —SR 5 , alkyl, cycloalkyl, haloalkyl, —NR 5 R 5 , and —OR 5 ;
each R 5 is independently H, alkyl, haloalkyl, arylalkyl, or heteroalkyl;
R 6 is OH or —NR 5 R 5 ;
each R 7 is independently selected from H, alkyl, haloalkyl, arylalkyl, and heteroalkyl;
m and n are independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;
r is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
s is 1, 2, 3, 4, or 5;
k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
p is 2, 3, 4, 5, 6, 7, 8, 9, or 10; and
q is 2, 3, 4, 5, 6, 7, 8, 9, or 10.
5. The LC of claim 1 , wherein the LC is selected from the following:
6. A pharmaceutical composition comprising the LC of claim 1 .
7. A method for treating a disease or condition selected from acute heart failure, congestive heart failure, compensated heart failure, decompensated heart failure, scleroderma, diffuse scleroderma, systemic scleroderma, fibromyalgia, fibrosis, and preeclampsia; or inducing labor in a subject in need thereof, the method comprising administering to the subject a composition comprising a therapeutically effective amount of the LC of claim 1 .
8. The method of claim 7 , wherein the LC is administered with one or more additional therapeutic agents selected from a group consisting of an anti-inflammatory drug, a statin, a diuretic, a beta-blocker, an angiotensin converting enzyme inhibitor, an angiotensin II receptor blocker or any combination thereof.