Orally administered composition of methioninase enzyme
Inventors
Han, Qinghong • Hoffman, Robert M
Assignees
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Publication Number
US-11371036-B2
Publication Date
2022-06-28
Expiration Date
Abstract
A composition and method for lowing serum and plasma levels of methionine by oral administration. The composition includes a recombinant methioninase enzyme and a cofactor (pyridoxal-L-phosphate). Methods of use describe methods for treatment of cancer, including malignant melanoma, by oral administration of the methioninase composition. Methods for chronic suppressive therapy of melanoma and other cancers are described. Because reduction of plasma methionine levels is effective in treating other conditions, including diabetes and conditions associated with aging, the use of the methods described herein includes treatment of these and other conditions.
Core Innovation
The invention describes an orally administered recombinant methioninase (rMETase) composition that reduces serum methionine levels in an individual in need thereof. The composition comprises a methioninase enzyme, pyridoxal-L-phosphate (PLP) as a cofactor, and a phosphate-buffered saline (PBS) solution.
The disclosed problem is that methionine dependence in cancers motivates lowering serum or plasma methionine as a therapeutic approach. The background rationale supports using methioninase activity to reduce plasma methionine levels, including in the context of tumor growth inhibition.
Oral rMETase is characterized as more effective than intraperitoneal rMETase when administered together with PLP in drinking water. In the described melanoma PDOX study, oral dosing is associated with reduced tumor growth and plasma methionine levels, with reported safety outcomes including no observed body weight loss or deaths.
Claims Coverage
The provided claim set covers an oral composition to reduce serum methionine levels, with three core inventive features. The dependents further specify PLP concentration and methioninase amount by body weight for an oral unit dose form.
Oral methioninase/PLP/PBS composition for lowering serum methionine
A composition for oral administration to reduce serum methionine levels in an individual in need thereof comprising a methioninase enzyme, pyridoxal-L-phosphate as a cofactor, and a phosphate-buffered saline solution.
PLP aqueous concentration for the oral composition
The composition includes pyridoxal-L-phosphate in an aqueous solution at about 20 millimoles per liter of water.
Body-weight-normalized methioninase enzyme amount for an oral unit dose form
The oral unit dose form includes methioninase enzyme at about 100 mg per kilogram of the individual’s body weight.
Overall, the claims center on an orally administered methioninase composition that includes PLP and PBS, with dependent limitations specifying PLP concentration in aqueous solution and methioninase amount normalized to body weight for an oral unit dose form.
Stated Advantages
Reduces serum methionine levels, including plasma methionine levels.
Oral rMETase is more effective than intraperitoneal rMETase when administered with PLP in drinking water.
In the described melanoma PDOX study, reduced tumor growth is observed.
Reported safety outcomes include no observed body weight loss and no deaths.
Documented Applications
Cancer treatment, including malignant melanoma (BRAF-V600E melanoma PDOX) and Ewing’s sarcoma.
Insulin-resistant diabetes mellitus.
Aging-related conditions, including life extension.
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