Pharmaceutical composition comprising erythrocytes encapsulating a PLP-dependent enzyme and, a non-phosphate PLP precursor
Inventors
Godfrin, Yann • Bourgeaux, Vanessa • GAY, Fabien • CORTESE, Thomas
Assignees
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Publication Number
US-11458170-B2
Publication Date
2022-10-04
Expiration Date
Abstract
The invention relates to a pharmaceutical composition containing a PLP-dependent enzyme and optionally its cofactor, pyridoxal phosphate (PLP), and/or a phosphate or non-phosphate precursor of PLP, its use as a drug, its production method and a therapeutic treatment method related to it. The pharmaceutical composition comprises erythrocytes and a pharmaceutically acceptable vehicle, the erythrocytes encapsulating the PLP-dependent enzyme. The PLP-dependent enzyme may be methioninase, tyrosine phenol-lyase, tyrosine aminotransferase or cystathionine beta-synthase.
Core Innovation
The invention relates to a pharmaceutical composition comprising one or more erythrocyte(s) encapsulating a plurality of pyridoxal phosphate (PLP)-dependent enzyme molecules. The erythrocytes include a sufficient amount of pyridoxine kinase (PN-kinase) and pyridoxine phosphate oxidase (PNP oxidase) to produce PLP from a PLP precursor present in a subject’s bloodstream, thereby maintaining a sufficient portion of the encapsulated PLP-dependent enzyme molecules in their holoenzyme forms to preserve enzymatic activity after administration.
The problem addressed is that systemic PLP enzymes face immunogenicity and a short plasma half-life, and cofactor bioavailability is rapidly lost after administration. Prior cofactor supplementation is described as insufficient to maintain enzymatic function in vivo, so the invention aims to keep the enzyme in holoenzyme form by increasing or maintaining intracellular PLP in erythrocytes rather than relying only on systemic PLP availability.
The composition and rationale are further described in connection with therapeutic substrate depletion beyond 24 hours after injection or infusion, including longer persistence as mapped in the document. This includes targeted depletion of substrates such as methionine and tyrosine for anticancer use, and depletion involving homocysteine and tyrosine for cardiovascular, neurologic, ocular, and skeletal disorders, as well as Richner-Hanhart syndrome through PLP-dependent enzyme activity maintained in the erythrocyte encapsulated form.
Claims Coverage
The patent document contains one independent claim and multiple dependent claims. Across the claims, the main inventive features are directed to erythrocyte encapsulation of PLP-dependent enzymes combined with erythrocyte internal capability to generate PLP from a bloodstream PLP precursor, thereby maintaining holoenzyme activity beyond 24 hours after injection or infusion, with further refinements for persistence/measurement, selectable enzyme types, optional inhibitor of PLP-phosphatase, and defined concentration ranges for encapsulated PLP/PNP/PMP per liter of erythrocytes.
Erythrocytes encapsulating plural PLP-dependent enzymes with in-erythrocyte PLP generation
One or more erythrocyte(s) encapsulating a plurality of pyridoxal phosphate (PLP)-dependent enzyme molecules, the erythrocytes comprising a sufficient amount of pyridoxine kinase (PN-kinase) and pyridoxine phosphate oxidase (PNP oxidase) to produce a sufficient amount of PLP from PLP precursor present in a subject's bloodstream.
Maintaining holoenzyme activity beyond 24 hours after administration
To maintain a sufficient portion of the erythrocyte-encapsulated PLP-dependent enzyme molecules in their holoenzyme forms to preserve enzymatic activity beyond 24 hours after injection or infusion into the subject in need of said enzymatic activity.
Holoenzyme persistence measured by plasma substrate depletion
Erythrocyte-encapsulated PLP-dependent activity that persists in a subject for at least 15 days after injection or infusion, as measured by plasma depletion exceeding 20%–50% of the PLP-dependent enzyme substrate.
Defined encapsulated PLP/PNP/PMP concentration per liter of erythrocytes
A composition that contains, per liter of erythrocytes, about 0.05 to 600 µmol of encapsulated PLP and/or pyridoxine phosphate (PNP) and/or pyridoxamine phosphate (PMP).
Selection of PLP-dependent enzyme types
The PLP-dependent enzyme is selected from methioninase, tyrosine phenol-lyase, tyrosine aminotransferase, or cystathionine beta-synthase.
Phosphate precursor identity
The phosphate precursor in the composition is selected from pyridoxine phosphate (PNP), pyridoxamine phosphate (PMP), or mixtures thereof.
Inhibition of PLP-phosphatase
A composition that includes pyridoxine kinase (PN-kinase), pyridoxine phosphate oxidase (PNP-oxidase), and an agent that inhibits pyridoxal phosphate phosphatase (PLP-phosphatase) in addition to the composition.
Overall, the claim set centers on erythrocyte encapsulation of PLP-dependent enzymes together with PN-kinase and PNP oxidase activities to generate PLP from a PLP precursor in the subject’s bloodstream, thereby maintaining the encapsulated enzymes in holoenzyme form for preserved enzymatic activity beyond 24 hours. Dependent claims further specify persistence using plasma substrate depletion criteria, provide concentration ranges for encapsulated PLP/PNP/PMP per liter of erythrocytes, narrow selectable PLP-dependent enzymes, define phosphate precursor selection, and optionally include an agent inhibiting PLP-phosphatase.
Stated Advantages
Preserves enzymatic activity beyond 24 hours after injection or infusion by maintaining PLP-dependent enzymes in their holoenzyme forms.
Enables PLP-dependent activity to persist for at least 15 days, as measured by plasma depletion exceeding 20%–50% of the PLP-dependent enzyme substrate.
Documented Applications
Anticancer use involving depletion of methionine and tyrosine through maintained PLP-dependent enzyme activity.
Cardiovascular, neurologic, ocular, and skeletal disorder use involving depletion involving homocysteine and tyrosine.
Richner-Hanhart syndrome use involving maintained PLP-dependent enzyme activity.
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