Methods and compositions for increasing α-L-iduronidase activity in the CNS
First Claim
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1. A method of treating a central nervous system α
- -L-iduronidase deficiency in a subject in need thereof, comprising systemically administering to the subject in need thereof a therapeutically effective dose of a fusion antibody having α
-L-iduronidase activity, wherein;
(a) at least about 25,000 units of α
-L-iduronidase activity are delivered to a brain tissue of the subject in need thereof;
(b) the therapeutically effective dose of a fusion antibody having α
-L-iduronidase activity comprises at least about 200,000 units of α
-L-iduronidase activity/Kg of body weight;
(c) the fusion antibody having α
-L-iduronidase activity comprises a fusion protein comprising an amino acid sequence of an immunoglobulin heavy chain and an α
-L-iduronidase;
(d) the fusion antibody having α
-L-iduronidase activity binds to an endogenous receptor of a blood brain barrier (BBB) transport system; and
(e) the amino acid sequence of the α
-L-iduronidase is covalently linked at its amino terminus to the carboxy terminus of the amino acid sequence of the immunoglobulin heavy chain,wherein the α
-L-iduronidase retains at least 30% of its enzymatic activity compared to an unfused α
-L-iduronidase.
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Abstract
Provided herein are methods and compositions for treating a subject suffering from a deficiency in α-L-Iduronidase in the CNS. The methods include systemic administration of a bifunctional fusion antibody comprising an antibody to a human insulin receptor and an α-L-Iduronidase. A therapeutically effective systemic dose is based on the specific CNS uptake characteristics of human insulin receptor antibody-α-L-Iduronidase fusion antibodies as described herein.
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Citations
31 Claims
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1. A method of treating a central nervous system α
- -L-iduronidase deficiency in a subject in need thereof, comprising systemically administering to the subject in need thereof a therapeutically effective dose of a fusion antibody having α
-L-iduronidase activity, wherein;(a) at least about 25,000 units of α
-L-iduronidase activity are delivered to a brain tissue of the subject in need thereof;(b) the therapeutically effective dose of a fusion antibody having α
-L-iduronidase activity comprises at least about 200,000 units of α
-L-iduronidase activity/Kg of body weight;(c) the fusion antibody having α
-L-iduronidase activity comprises a fusion protein comprising an amino acid sequence of an immunoglobulin heavy chain and an α
-L-iduronidase;(d) the fusion antibody having α
-L-iduronidase activity binds to an endogenous receptor of a blood brain barrier (BBB) transport system; and(e) the amino acid sequence of the α
-L-iduronidase is covalently linked at its amino terminus to the carboxy terminus of the amino acid sequence of the immunoglobulin heavy chain,wherein the α
-L-iduronidase retains at least 30% of its enzymatic activity compared to an unfused α
-L-iduronidase. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25)
- -L-iduronidase deficiency in a subject in need thereof, comprising systemically administering to the subject in need thereof a therapeutically effective dose of a fusion antibody having α
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26. A method for treating a central nervous system α
- -L-iduronidase deficiency in a subject in need thereof, comprising systemically administering to the subject in need thereof a therapeutically effective dose of a fusion antibody having α
-L-iduronidase activity, wherein;(a) at least about 25,000 units of α
-L-iduronidase activity are delivered to a brain tissue of the subject in need thereof wherein the therapeutically effective dose comprises at least about 200,000 units of α
-L-iduronidase activity/Kg of body weight;(b) the fusion antibody having α
-L-iduronidase activity comprises;
(a) a fusion protein comprising the amino acid sequence of an immunoglobulin light chain that comprises a variable region and a constant region and an α
-L-iduronidase;(c) the fusion antibody having α
-L-iduronidase activity binds to an endogenous receptor of a blood brain barrier (BBB) transport system and catalyzes hydrolysis of unsulfated alpha-L-iduronosidic linkages in at least one of dermatan sulfate and heparan sulfate; and(d) the amino acid sequence of the α
-L-iduronidase is covalently linked at its amino terminus to the carboxy terminus of the amino acid sequence of the immunoglobulin light chain,wherein the α
-L-iduronidase retains at least 30% of its enzymatic activity compared to an unfused α
-L-iduronidase. - View Dependent Claims (27, 28, 29, 30, 31)
- -L-iduronidase deficiency in a subject in need thereof, comprising systemically administering to the subject in need thereof a therapeutically effective dose of a fusion antibody having α
Specification