Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-8513211-B2
Publication Date
2013-08-20
Expiration Date
Abstract
The present disclosure describes the broadly active chelation of diverse divalent 2+ metal cations by any oligonucleotide (ON), regardless of size or modification. This chelation effect is specific to cations which are divalent (or of higher valency) and results in the formation of oligonucleotide chelate complexes which do not behave like salts. It is described herein a novel composition of an ON chelate complex prepared using any ON and a divalent metal cation and methods for the suppression of anti-coagulation and or subcutaneous injection site reactions and or improved tolerability with oligonucleotides by the use of ON chelate complexes during oligonucleotide administration.
Core Innovation
The invention provides an oligonucleotide chelate complex in which at least two oligonucleotides are linked intermolecularly by a divalent cation. At least one oligonucleotide includes at least one phosphorothioate linkage, and the complex is formed as a soluble multimeric oligonucleotide chelate complex rather than as salts.
The chelate complex is characterized by metal specificity for divalent cations rather than monovalent cations, and by divalent-cation universality across a broad set of metals. Divalent cations explicitly include Ca, Mg, Co, Fe2+, Mn, Ba, Ni, Cu, Zn, Cd, Hg, and Pb.
The disclosure links calcium chelation to functional outcomes, including blood anti-coagulation and subcutaneous injection site reactions. It states that ON-induced anti-coagulation can be explained by calcium chelation, and that subcutaneous injection site reactions can be suppressed by administering the ONs as pre-formed calcium or other divalent metal chelate complexes.
Claims Coverage
The independent claim covers one inventive feature centered on a pharmaceutical composition comprising an oligonucleotide chelate complex formed from at least two oligonucleotides linked intermolecularly by a divalent cation, where at least one oligonucleotide includes phosphorothioate linkages, together with a pharmaceutically acceptable excipient. The dependent claims further specify metal classes, oligonucleotide chemistries, and subcutaneous administration.
Oligonucleotide chelate complex linked by divalent cations with phosphorothioate
An oligonucleotide chelate complex comprising at least two oligonucleotides linked intermolecularly by a divalent cation, wherein at least one oligonucleotide has at least one phosphorothioate linkage, together with a pharmaceutically acceptable excipient.
Divalent cation as alkali earth metal with 2+ charge state
The oligonucleotide chelate complex has a divalent cation that is an alkali earth metal with a 2+ charge state.
Divalent metal cation selected from listed metals
The oligonucleotide chelate complex has a divalent metal cation selected from calcium, magnesium, cobalt, iron (2+), manganese, copper or zinc.
At least one fully phosphorothioated oligonucleotide
The oligonucleotide chelate complex includes at least one fully phosphorothioated oligonucleotide.
Ribose each 2′-O-methylated oligonucleotide
The oligonucleotide chelate complex includes at least one oligonucleotide whose ribose is each 2′ O-methylated.
Adapted for subcutaneous administration
The pharmaceutical composition is adapted for subcutaneous administration.
Overall, the claim set centers on pharmaceutical compositions comprising soluble multimeric oligonucleotide chelate complexes in which at least two oligonucleotides are linked by a divalent cation with phosphorothioate-containing oligonucleotides, while dependent claims specify particular divalent metals, fully phosphorothioated and 2′-O-methylated oligonucleotides, and subcutaneous administration.
Stated Advantages
Suppression of ON-induced prothrombin time (PTT) changes via administration of ONs as pre-formed calcium or other divalent metal chelate complexes.
Improved subcutaneous tolerability, including suppression or reduction of subcutaneous injection site reactions such as induration, inflammation, tenderness, and pain.
Reduction of serum protein interactions and implications for serum half-life.
Prevention or correction of hypocalcemia in chronic treatment contexts.
Documented Applications
Use of ONs as pre-formed calcium or other divalent metal chelate complexes to suppress blood anti-coagulation and to reduce subcutaneous injection site reactions, including suppression of PTT changes and improved subcutaneous tolerability.
Interested in licensing this patent?