Dactinomycin compositions and methods for the treatment of myelodysplastic syndrome and acute myeloid leukemia
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Publication Number
US-11975111-B2
Publication Date
2024-05-07
Expiration Date
Abstract
The disclosure provides compositions comprising dactinomycin, formulated for delivery by nanoparticle, and methods for treating a myelodysplastic syndrome (MDS) or cancer, for example, NPM1-mutated acute myeloid leukemia (AML), by administration of the compositions of the disclosure.
Core Innovation
The invention describes administering a therapeutically effective amount of dactinomycin encapsulated in nanoparticles comprising PLA-mPEG to treat a myelodysplastic syndrome (MDS) in a subject in need thereof. The PLA-mPEG comprises about 25% mPEG by weight, has a molecular weight of about 30,000 Da, and the nanoparticles have an average size of about 100 nm to about 200 nm.
The method is defined by a pharmacokinetic outcome in the subject: administration results in a Cmax of dactinomycin of about 1 ng/mL to about 20 ng/mL. The disclosure further includes a surfactant including polyvinyl alcohol, defined dactinomycin loading by weight, and combination therapy using one or more chemotherapeutic drug classes together with dactinomycin.
The disclosed therapeutic framing also addresses treatment contexts including cancers, including NPM1-mutated acute myeloid leukemia (AML), through nanoparticle dactinomycin formulations based on PLA-mPEG and related polymer systems. Additional narrative describes extended release, increased stability, systemic exposure, and tolerability relative to free actinomycin-D, as well as mitigation of mucositis using anti-inflammatory agents and/or antioxidants.
Claims Coverage
The document provides one independent claim defining an MDS treatment method and several dependent claims that further refine the nanoparticle composition and permit combination therapy. The central inventive features are the use of PLA-mPEG nanoparticles with specified composition and size, encapsulated dactinomycin, and a resulting Cmax window in the subject.
Treating MDS with PLA-mPEG encapsulated dactinomycin nanoparticles
A method for treating a myelodysplastic syndrome (MDS) in a subject in need thereof comprising administering a therapeutically effective amount of a composition comprising dactinomycin encapsulated in nanoparticles comprising PLA-mPEG.
PLA-mPEG composition and nanoparticle size constraints
PLA-mPEG comprises about 25% mPEG by weight; the molecular weight of the PLA-mPEG is about 30,000 Da; and the nanoparticles have an average size of about 100 nm to about 200 nm.
Cmax-controlled systemic exposure after administration
The therapeutically effective amount of the composition, upon administration to the subject, results in a Cmax of dactinomycin of about 1 ng/mL to about 20 ng/mL.
Polyvinyl alcohol as a surfactant in the method
The method is carried out using polyvinyl alcohol as the surfactant.
Dactinomycin loading by weight constraint
The method is carried out using a composition that contains about 5% to about 15% by weight dactinomycin.
Combination therapy with defined molar ratios to dactinomycin
The method includes adding a therapeutically effective amount of at least one specified chemotherapeutic drug with dactinomycin, where the molar ratio between dactinomycin and the selected drug(s) is 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, <1:1, or any ratio in between.
Claim coverage centers on an MDS treatment method using dactinomycin encapsulated in PLA-mPEG nanoparticles with specific PLA-mPEG composition and nanoparticle size, together with an explicit Cmax window. Dependent claims further specify polyvinyl alcohol as a surfactant, a dactinomycin loading range, and combination therapy with specified chemotherapeutic drug classes under constrained molar ratios relative to dactinomycin.
Stated Advantages
Extended release, increased stability, and improved tolerability relative to free actinomycin-D.
Improved systemic exposure and increased Cmax/systemic levels for PEGylated polymers.
Mitigation of mucositis using anti-inflammatory agents and/or antioxidants and drug holidays.
Documented Applications
Treatment of myelodysplastic syndrome (MDS) in a subject in need thereof using dactinomycin encapsulated in PLA-mPEG nanoparticles.
Treatment of cancers including NPM1-mutated acute myeloid leukemia (AML) using nanoparticle dactinomycin formulations based on PLA-mPEG and related polymer systems.
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