PHARMACEUTICAL COMPOSITIONS FOR DELIVERY TO THE EYE
Aptamers are single-stranded RNA or DNA molecules that bind to target molecules by forming complex three-dimensional structures. Their target molecules vary widely—including proteins, peptides, carbohydrates, lipids, small compounds, and metal ions—and because of their strong binding affinity and high specificity, aptamers have been put to practical use in fields such as therapeutics, diagnostics, and separation technologies. As pharmaceuticals, the world's first aptamer drug, Macugen®, was approved in the United States in 2004 as a treatment for neovascular age-related macular degeneration, and several other aptamers are now in clinical development. Research is also progressing on their use as tools in drug delivery systems (DDS), and the importance of aptamers in the pharmaceutical field is expected to continue growing. In this article, we provide an overview of aptamer acquisition methods and optimization strategies for therapeutic use, and introduce the latest developments in aptamer-based drugs currently in clinical trials.
1 . A composition comprising a non-pegylated aptamer 5′ NH 2 -fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGf UfUfUAfCfCfUmGf CmG-3T-3′ (SEQ ID NO: 1), wherein:
(a) more than 85% of the aptamer in the composition is full length aptamer, and wherein the composition comprises:
(b) less than 1.8% of G cleavage products,
(c) 1% or less of deprotection failure products,
(d) less than 0.1% of A cleavage products,
(e) less than 1.1% of n−4, n−3 and n−2 deletion products, and
(f) less than 3% of fluoro degradants and n−1 deletion products.
2 . The composition of claim 1 , wherein:
(a) 88.3%-91.8% of the aptamer in the composition is full length aptamer; and wherein the composition comprises:
(b) 1.06%-1.71% of G cleavage products,
(c) 0.55%-1.00% of deprotection failure products,
(d) 0%-0.08% of A cleavage products, and
(e) 2.12%-2.86% of fluoro degradants and n−1 deletion products.
3 . A composition, comprising a PEGylated aptamer having the structure:
or a salt thereof, wherein the aptamer comprises the sequence of SEQ ID NO: 1, wherein:
(a) more than 92% of the aptamer in the composition is full length aptamer; and
(b) less than 5% of the composition is relative retention time 2 (RRT2) (>full length product (FLP)-≤1.2).
4 . The composition of claim 3 , wherein:
(a) 93.0%-94.0% of the aptamer in the composition is full length aptamer,
(b) 3.00%-4.74% of the composition is RRT 2 (>FLP-≤1.20), and
(c) 1.97%-2.65% of the composition is RRT 1 (≥0.93-<FLP).
5 . The composition of claim 3 , wherein the PEGylated aptamer comprises a 2-arm branched PEG ranging from approximately 39 kDa to approximately 47 kDa.
6 . The composition of claim 3 , wherein the PEGylated aptamer comprises a 2-arm branched PEG of approximately 40 kDa.
7 . The composition of claim 3 , wherein the PEGylated aptamer comprises a 2-arm branched PEG of approximately 43 kDa.
8 . The composition of claim 3 , wherein the salt is a sodium salt.
9 . The composition of claim 8 , wherein the composition is at least 5% more potent at inducing a complement cascade as measured by ELISA, as compared to a control composition, wherein:
(a) 90.6% of the aptamer in the control composition is full length product,
(b) 1.3% of the control composition is RRT 1 (≥0.93-<FLP), and
(c) 8.15% of the control composition is RRT 2 (>FLP-≤1.20).
10 . The composition of claim 3 , comprising one or more pharmaceutically acceptable excipients.
11 . The composition of claim 3 , wherein the composition is a sterile aqueous solution comprising 20 mg/mL of the aptamer and phosphate-buffered saline and having a pH in the range of 6.8-7.8.
12 . The composition of claim 11 , wherein the composition has a pH of 7.3.
13 . The composition of claim 3 , wherein the composition has an osmolality between 350 mOsM/kg to 500 mOsM/kg.
14 . A method for treating geographic atrophy secondary to age-related macular degeneration, the method comprising intravitreally administering to a subject in need thereof, the composition of claim 3 at a dose between about 1 mg/eye to about 5 mg/eye.
15 . The method of claim 14 , comprising administering the composition at a dose of about 2 mg/eye.
16 . The method of claim 14 , comprising injecting about 100 μL of the composition per eye.
17 . The method of claim 14 , wherein the dose is administered once monthly.
18 . The method of claim 14 , wherein the dose is administered once every 28±7 days.