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Publication Number
US-8716259-B2
Publication Date
2014-05-06
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 relates to oligonucleotide chelate complexes formed when oligonucleotides bind multivalent divalent metal cations. The binding creates non-salt, multimeric oligonucleotide-metal species that are soluble at certain concentrations, and the complexes sequester divalent cations, including calcium and magnesium, including mixed magnesium/calcium chelate complexes.
The chelation mechanism is used to address clinically relevant oligonucleotide side effects associated with administration. The document links divalent cation chelation to suppressing or reducing the anticoagulation effect of an oligonucleotide administration, including anti-coagulation activity associated with prothrombin time, and further associates the chelate approach with reduced serum protein interactions and shorter serum half-life.
The chelate complexes are also described as improving tolerability in subject administration settings. The document links administration as calcium chelates to mitigation of subcutaneous injection site reactions and to prevention of hypocalcemia during chronic dosing, with mechanistic and experimental support using fluorescence polarization and observations with human blood and patient context.
Claims Coverage
The independent claim family member describes a method of administering an oligonucleotide as a chelate complex to suppress or reduce anticoagulation effects, suppress or reduce subcutaneous injection site reactions, or improve IV infusion tolerability. The claim structure centers on a chelate complex where at least two oligonucleotides are linked intermolecularly by a divalent cation, with dependent claims specifying the divalent cation type and additional oligonucleotide chemistry constraints as inventive feature refinements.
Administering a chelate complex linked by a divalent cation
Administering the oligonucleotide to the subject as a chelate complex, the chelate complex comprising at least two oligonucleotides linked intermolecularly by a divalent cation.
Calcium chelate complex
The method further comprises administering the oligonucleotide as a calcium chelate complex.
Magnesium chelate complex
The method further comprises administering the oligonucleotide as a magnesium chelate complex.
Oligonucleotide containing 5-methylcytosine
The method further comprises administering a chelate complex that contains an oligonucleotide including at least one 5-methylcytosine.
Oligonucleotide containing phosphorothioate linkages
The method further comprises administering a chelate complex that includes at least one oligonucleotide containing at least one phosphorothioate linkage.
Pharmaceutically acceptable excipient included in chelate complex
The method further comprises administering a chelate complex that includes a pharmaceutically acceptable excipient.
Across the independent-claim approach, the coverage is anchored in administering an oligonucleotide as a chelate complex where at least two oligonucleotides are linked intermolecularly by a divalent cation. Dependent refinements narrow the divalent cation to calcium or magnesium and further specify oligonucleotide modifications and inclusion of a pharmaceutically acceptable excipient.
Stated Advantages
Suppressing or reducing the anticoagulation effect of an oligonucleotide administration.
Suppressing or reducing subcutaneous injection site reactions of the oligonucleotide administration.
Improving the tolerability of the oligonucleotide when administered by IV infusion.
Documented Applications
Use of chelate complex administration to suppress or reduce anticoagulation effect of an oligonucleotide administration in a subject.
Use of chelate complex administration to suppress or reduce subcutaneous injection site reactions in a subject.
Use of chelate complex administration to improve tolerability when an oligonucleotide is administered by IV infusion in a subject.
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