Method of treating a mammal, including human, against cancer using methionine and asparagine depletion
Inventors
AGUERA, Karine • BERLIER, Willy • GAY, Fabien • Godfrin, Yann
Assignees
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Publication Number
US-11141468-B2
Publication Date
2021-10-12
Expiration Date
Abstract
The invention is related to a new method for treating liquid and solid cancers, in a mammal, including human, wherein methioninase is administered before asparaginase. The invention also encompasses the use of a dietary methionine deprivation, possibly combined with methioninase administration, in advance of asparaginase treatment. Methioninase and asparaginase may be used in particular under free form, pegylated form or encapsulated into erythrocytes.
Core Innovation
The invention relates to a method for treating cancer in a mammal by inducing methionine deprivation and then inducing asparagine deprivation. The approach administers a composition comprising methioninase and then a composition containing an asparaginase, with a delay between the end of methioninase administration and the initiation of asparaginase administration.
The delay is constrained into defined windows that depend on the methioninase formulation. For methioninase in free form or pegylated, the delay is between about 1 h and about 7 days, between about 3 h and about 6 days, or between about 1 day and 5 days, while for methioninase encapsulated into erythrocytes the delay is between about 1 day and about 20 days, or between about 1 day and about 10 days.
The regimen further supports methioninase formulations including free enzyme form, pegylated enzyme, and erythrocyte encapsulation, including RBC-encapsulated formats. Formulation options include combinations such as ERY-MET and ERY-ASP, and the sequence concept includes pyridoxal phosphate (PLP) and precursors of vitamin B6 such as pyridoxine (PN), pyridoxine phosphate (PNP), and pyridoxamine phosphate (PMP).
The invention also documents sequential administration and a timing-dependent outcome, describing surprising in vitro synergy when methionine deprivation is induced first and MGL is added followed by L-asparaginase after 3–4 days, contrasted with loss of benefit when the order is reversed. Experimental examples include in vitro and in vivo efficacy in gastric tumor xenografts, as well as encapsulation formats intended to reduce allergic reactions.
Claims Coverage
The partial content includes one independent claim. It defines a sequential cancer treatment method with a defined inter-enzyme delay window that varies with the methioninase formulation, and it constrains the delay ranges for free/pegylated versus erythrocyte-encapsulated methioninase.
Sequential methioninase then asparaginase for cancer treatment with a defined delay window
Administering to a mammal in need thereof a composition comprising a methioninase and then a composition containing an asparaginase, wherein there is a delay of between about 1 h and about 30 days between the end of the methioninase administration and the initiation of the asparaginase administration.
Form-dependent delay ranges for free or pegylated methioninase
When methioninase is under free form or is pegylated, the delay is between about 1 h and about 7 days, between about 3 h and about 6 days, or between about 1 day and 5 days.
Form-dependent delay ranges for erythrocyte-encapsulated methioninase
When methioninase is encapsulated into erythrocytes, the delay is between about 1 day and about 20 days, or between about 1 day and about 10 days.
Erythrocyte encapsulation of methioninase and asparaginase
Administering methioninase and asparaginase encapsulated into erythrocytes, optionally using a hypoosmotic encapsulation method for the erythrocytes.
Constrained methioninase-to-asparaginase delay to a 1–10 day window
Carrying out the method such that the delay between ending methioninase administration and starting asparaginase administration is between about 1 day and about 10 days.
Methioninase dosing range in IU
Administering methioninase one or more times at a dose between about 100 and about 100,000 IU.
Asparaginase dosing range in IU
Administering asparaginase one or more times at a dose amount between about 500 and about 100,000 IU, or between about 1,000 and about 50,000 IU.
PLP or PLP precursor timing around methioninase before asparaginase
Administering methioninase at least once or twice before administering asparaginase, with each methioninase administration being accompanied or followed by administration of PLP or a PLP precursor before the asparaginase administration.
The core claim coverage is the sequential administration of methioninase followed by asparaginase with a delay window that depends on whether methioninase is free/pegylated versus erythrocyte-encapsulated, optionally combined with erythrocyte encapsulation of both enzymes and PLP or precursor timing around methioninase before asparaginase. The refinements also specify a 1–10 day delay window and IU dosing ranges for methioninase and asparaginase.
Stated Advantages
Surprising in vitro synergy when methionine deprivation is induced first and asparaginase is initiated after a delay, contrasted with loss of benefit when the order is reversed.
Efficacy described in vivo for gastric tumor xenografts.
Formulation options include strategies intended to reduce allergic reactions.
Documented Applications
Treating cancer in a mammal by inducing methionine deprivation with methioninase followed by asparagine deprivation with asparaginase, using defined inter-enzyme delays.
In vitro use supporting synergy associated with sequential methionine deprivation and then asparagine deprivation with timing constraints.
In vivo use showing efficacy in gastric tumor xenografts.
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