Synthetic hyperglycosylated, protease-resistant polypeptide variants, oral formulations and methods of using the same
First Claim
1. An oral pharmaceutical composition comprising:
- (a) a first number of moles of a known protease-resistant or protease-resistant, hyperglycosylated polypeptide variant of a parent protein therapeutic in a first unit form, the known protease-resistant or protease-resistant, hyperglycosylated polypeptide variant comprising at least one mutated protease cleavage site in place of a native protease cleavage site found in the parent protein therapeutic, and further comprising;
i) a carbohydrate moiety covalently attached to at least one non-native glycosylation site that is not present in the parent protein therapeutic;
or ii) a carbohydrate moiety covalently attached to at least one native glycosylation site that is present but is not glycosylated in the parent protein therapeutic; and
(b) a pharmaceutical excipient suitable for oral delivery, wherein the first number of moles of the known protease-resistant or protease-resistant, hyperglycosylated polypeptide variant in the first unit form is greater than a second number of moles of the parent protein therapeutic in a parenteral pharmaceutical composition, wherein the parenteral pharmaceutical composition is an immediate release formulation suitable for subcutaneous bolus injection;
wherein the parent protein therapeutic is proven to be effective in the treatment of a disease in a patient when administered to the patient by subcutaneous bolus injection of an amount of the parenteral pharmaceutical composition whereby the patient receives the second number of moles of the parent protein therapeutic at a selected dosing interval; and
wherein, upon oral administration of the first unit form to a patient, the time required for release of the first number of moles of the known protease-resistant or protease-resistant, hyperglycosylated polypeptide variant is no more than the time between doses in the selected dosing interval.
4 Assignments
0 Petitions
Accused Products
Abstract
The present invention provides synthetic Type I interferon receptor polypeptide agonists comprising consensus or hybrid Type I interferon receptor polypeptide agonists, containing one or more native or non-native glycosylation sites. The present invention further provides oral formulations of protease-resistant or protease-resistant, hyperglycosylated polypeptide variants, which polypeptide variants lack at least one protease cleavage site found in a parent polypeptide, and thus exhibit increased protease resistance compared to the parent polypeptide, which polypeptide variants further include (1) a carbohydrate moiety covalently linked to at least one non-native glycosylation site not found in the parent protein therapeutic or (2) a carbohydrate moiety covalently linked to at least one native glycosylation site found but not glycosylated in the parent protein therapeutic. The present invention further provides compositions, including oral pharmaceutical compositions, comprising the synthetic Type I interferon receptor polypeptide agonist, the hyperglycosylated polypeptide variant, the protease-resistant polypeptide variant, or the hyperglycosylated, protease-resistant polypeptide variant. The present invention further provides containers, devices, and kits comprising the synthetic Type I interferon receptor polypeptide agonist, the hyperglycosylated polypeptide variant, the protease-resistant polypeptide variant, or the hyperglycosylated, protease-resistant polypeptide variant. The present invention further provides therapeutic methods involving administering an effective amount of an oral pharmaceutical composition comprising a synthetic Type I interferon receptor polypeptide agonist, a hyperglycosylated polypeptide variant, a protease-resistant polypeptide variant, or a hyperglycosylated, protease-resistant polypeptide variant to an individual in need thereof.
-
Citations
59 Claims
-
1. An oral pharmaceutical composition comprising:
-
(a) a first number of moles of a known protease-resistant or protease-resistant, hyperglycosylated polypeptide variant of a parent protein therapeutic in a first unit form, the known protease-resistant or protease-resistant, hyperglycosylated polypeptide variant comprising at least one mutated protease cleavage site in place of a native protease cleavage site found in the parent protein therapeutic, and further comprising;
i) a carbohydrate moiety covalently attached to at least one non-native glycosylation site that is not present in the parent protein therapeutic;
or ii) a carbohydrate moiety covalently attached to at least one native glycosylation site that is present but is not glycosylated in the parent protein therapeutic; and
(b) a pharmaceutical excipient suitable for oral delivery, wherein the first number of moles of the known protease-resistant or protease-resistant, hyperglycosylated polypeptide variant in the first unit form is greater than a second number of moles of the parent protein therapeutic in a parenteral pharmaceutical composition, wherein the parenteral pharmaceutical composition is an immediate release formulation suitable for subcutaneous bolus injection;
wherein the parent protein therapeutic is proven to be effective in the treatment of a disease in a patient when administered to the patient by subcutaneous bolus injection of an amount of the parenteral pharmaceutical composition whereby the patient receives the second number of moles of the parent protein therapeutic at a selected dosing interval; and
wherein, upon oral administration of the first unit form to a patient, the time required for release of the first number of moles of the known protease-resistant or protease-resistant, hyperglycosylated polypeptide variant is no more than the time between doses in the selected dosing interval. - View Dependent Claims (8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 23, 24, 34, 35)
-
-
2. An oral pharmaceutical composition comprising:
-
(a) a first dose of a known protease-resistant or protease-resistant, hyperglycosylated polypeptide variant of a parent protein therapeutic in a first unit form, the known protease-resistant or protease-resistant, hyperglycosylated polypeptide variant comprising at least one mutated protease cleavage site in place of a native protease cleavage site found in the parent protein therapeutic, and further comprising;
i) a carbohydrate moiety covalently attached to at least one non-native glycosylation site that is not present in the parent protein therapeutic;
or ii) a carbohydrate moiety covalently attached to at least one native glycosylation site that is present but is not glycosylated in the parent protein therapeutic; and
(b) a pharmaceutical excipient suitable for oral delivery, wherein the parent protein therapeutic is proven to be effective in the treatment of a disease in a patient when administered to the patient by subcutaneous bolus injection of a second dose of the parent protein therapeutic at a selected dosing interval;
wherein the amount of the known protease-resistant or protease-resistant, hyperglycosylated polypeptide variant in moles of drug per kilogram of patient body weight in the first dose is greater than the amount of parent protein therapeutic in moles of drug per kilogram of patient body weight in the second dose when the first and second doses are calculated for the average patient body weight in the total population of patients suffering from the disease; and
wherein, upon oral administration of the first dose in the first unit form to a patient, the time required for release of all of the known protease-resistant or protease-resistant, hyperglycosylated polypeptide variant in the first dose is no greater than the time between doses in the selected dosing interval. - View Dependent Claims (5, 6, 7)
-
-
3. An oral pharmaceutical composition comprising:
-
(a) a first number of moles of a known hyperglycosylated polypeptide variant of a parent protein therapeutic in a first unit form, the known hyperglycosylated polypeptide variant comprising;
i) a carbohydrate moiety covalently attached to at least one non-native glycosylation site that is not present in the parent protein therapeutic;
or ii) a carbohydrate moiety covalently attached to at least one native glycosylation site that is present but is not glycosylated in the parent protein therapeutic; and
(b) a pharmaceutical excipient suitable for oral delivery, wherein the first number of moles of the known hyperglycosylated polypeptide variant in the first unit form is greater than a second number of moles of the parent protein therapeutic in a parenteral pharmaceutical composition, wherein the parenteral pharmaceutical composition is an immediate release formulation suitable for subcutaneous bolus injection;
wherein the parent protein therapeutic is proven to be effective in the treatment of a disease in a patient when administered to the patient by subcutaneous bolus injection of an amount of the parenteral pharmaceutical composition whereby the patient receives the second number of moles of the parent protein therapeutic at a selected dosing interval; and
wherein, upon oral administration of the first unit form to a patient, the time required for release of the first number of moles of the known protease-resistant or protease-resistant, hyperglycosylated polypeptide variant is no more than the time between doses in the selected dosing interval.
-
-
4. An oral pharmaceutical composition comprising:
-
(a) a first dose of a known hyperglycosylated polypeptide variant of a parent protein therapeutic in a first unit form, the known hyperglycosylated polypeptide variant comprising;
i) a carbohydrate moiety covalently attached to at least one non-native glycosylation site that is not present in the parent protein therapeutic;
or ii) a carbohydrate moiety covalently attached to at least one native glycosylation site that is present but is not glycosylated in the parent protein therapeutic; and
(b) a pharmaceutical excipient suitable for oral delivery, wherein the parent protein therapeutic is proven to be effective in the treatment of a disease in a patient when administered to the patient by subcutaneous bolus injection of a second dose of the parent protein therapeutic at a selected dosing interval;
wherein the amount of the known hyperglycosylated polypeptide variant in moles of drug per kilogram of patient body weight in the first dose is greater than the amount of parent protein therapeutic in moles of drug per kilogram of patient body weight in the second dose when the first and second doses are calculated for the average patient body weight in the total population of patients suffering from the disease; and
wherein, upon oral administration of the first dose in the first unit form to a patient, the time required for release of all of the known hyperglycosylated polypeptide variant in the first dose is no greater than the time between doses in the selected dosing interval.
-
-
21. The composition of any of claim 120 wherein the known protease-resistant or protease-resistant, hyperglycosylated polypeptide variant comprises a carbohydrate moiety covalently attached at each glycosylation site in the polypeptide variant.
-
25. A method of treating a disease in a patient, the method comprising:
-
administering orally to the patient an oral pharmaceutical composition comprising a first number of moles of a known protease-resistant or protease-resistant, hyperglycosylated polypeptide variant of a parent protein therapeutic, in an amount whereby the patient receives the first number of moles of the known protease-resistant or protease-resistant, hyperglycosylated polypeptide variant at a first dosing interval, the known protease-resistant or protease-resistant, hyperglycosylated polypeptide variant comprising at least one mutated protease cleavage site in place of a native protease cleavage site found in the parent protein therapeutic, and further comprising;
i) a carbohydrate moiety covalently attached to at least one non-native glycosylation site that is not present in the parent protein therapeutic;
or ii) a carbohydrate moiety covalently attached to at least one native glycosylation site that is present but is not glycosylated in the parent protein therapeutic;
wherein the first number of moles of the known protease-resistant or protease-resistant, hyperglycosylated polypeptide variant is greater than a second number of moles of the parent protein therapeutic in a parenteral pharmaceutical composition, wherein the parenteral pharmaceutical composition is an immediate release formulation suitable for subcutaneous bolus injection;
wherein the parent protein therapeutic is proven to be effective in the treatment of the disease in a patient when administered to the patient by subcutaneous bolus injection of an amount of the parenteral pharmaceutical composition whereby the patient receives the second number of moles of the parent protein therapeutic at a second dosing interval; and
wherein the first dosing interval is the same as or shorter than the second dosing interval. - View Dependent Claims (36, 37, 38)
-
-
26. A method of treating a disease in a patient, the method comprising:
-
administering orally to the patient an oral pharmaceutical composition comprising a known protease-resistant or protease-resistant, hyperglycosylated polypeptide variant of a parent protein therapeutic, in an amount whereby the patient receives a first dose of the known protease-resistant or protease-resistant, hyperglycosylated polypeptide variant at a first dosing interval, the known protease-resistant or protease-resistant, hyperglycosylated polypeptide variant comprising at least one mutated protease cleavage site in place of a native protease cleavage site found in the parent protein therapeutic, and further comprising;
i) a carbohydrate moiety covalently attached to at least one non-native glycosylation site that is not present in the parent protein therapeutic;
or ii) a carbohydrate moiety covalently attached to at least one native glycosylation site that is present but is not glycosylated in the parent protein therapeutic;
wherein a parenteral pharmaceutical composition comprising the parent protein therapeutic is proven to be effective in the treatment of the disease in a patient when administered to the patient by subcutaneous bolus injection of an amount of the parenteral pharmaceutical composition whereby the patient receives a second dose of the parent protein therapeutic at a second dosing interval, wherein the first dose in moles of the known protease-resistant or protease-resistant, hyperglycosylated polypeptide variant per kilogram of patient body weight is greater than the second dose in moles of the parent protein therapeutic per kilogram of patient body weight when the first and second doses are calculated for the same patient body weight, and wherein, upon oral administration of the first dose to the patient, the time required for release of all of the known protease-resistant or protease-resistant, hyperglycosylated polypeptide variant in the first dose is no greater than the time between doses in the second dosing interval. - View Dependent Claims (27, 29, 30, 31, 32, 33)
-
-
28. A method of treating a disease in a patient, the method comprising:
-
administering orally to the patient an oral pharmaceutical composition comprising a known protease-resistant or protease-resistant, hyperglycosylated polypeptide variant of a parent protein therapeutic, in an amount whereby the patient receives a first dose of the known protease-resistant or protease-resistant, hyperglycosylated polypeptide variant at a first dosing interval, the known protease-resistant or protease-resistant, hyperglycosylated polypeptide variant comprising at least one mutated protease cleavage site in place of a native protease cleavage site found in the parent protein, and further comprising;
i) a carbohydrate moiety covalently attached to at least one non-native glycosylation site that is not present in the parent protein therapeutic;
or ii) a carbohydrate moiety covalently attached to at least one native glycosylation site present in but not glycosylated in the parent protein therapeutic;
wherein a parenteral pharmaceutical composition comprising the parent protein therapeutic is proven to be effective in the treatment of the disease in a patient when administered to the patient by subcutaneous bolus injection in an amount whereby the patient receives a second dose of the parent protein therapeutic at a second dosing interval, wherein the first dose in moles of the known protease-resistant or protease-resistant, hyperglycosylated polypeptide variant per kilogram of patient body weight is greater than the second dose in moles of the parent protein therapeutic per kilogram of patient body weight when the first and second doses are calculated for the same patient body weight, and wherein the time period between doses in the first dosing interval is the same as or shorter than the time period between doses in the second dosing interval.
-
- 39. A synthetic Type I interferon receptor polypeptide agonist.
Specification