Methods and compositions for increasing α-L-iduronidase activity in the CNS
First Claim
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1. A method for treating an α
- -L-iduronidase deficiency in the central nervous system of a subject in need thereof, comprising systemically administering to the subject a therapeutically effective dose of a fusion antibody having α
-L-iduronidase activity, wherein;
(i) at least about 25,000 units of α
-L-iduronidase activity are delivered to the brain wherein the therapeutically effective dose comprises at least about 1×
106 units of α
-L-iduronidase activity or at least about 200,000 units/Kg of body weight;
(ii) the fusion antibody comprises;
(a) a fusion protein containing the amino acid sequence of an immunoglobulin heavy chain and an α
-L-iduronidase, and (b) an immunoglobulin light chain that comprises a variable region and a constant region;
(iii) the fusion antibody binds to an endogenous receptor of a blood brain barrier (BBB) transport system and catalyzes hydrolysis of unsulfated alpha-L-iduronosidic linkages in dermatan sulfate; and
(iv) 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 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.
101 Citations
13 Claims
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1. A method for treating an α
- -L-iduronidase deficiency in the central nervous system of a subject in need thereof, comprising systemically administering to the subject a therapeutically effective dose of a fusion antibody having α
-L-iduronidase activity, wherein;(i) at least about 25,000 units of α
-L-iduronidase activity are delivered to the brain wherein the therapeutically effective dose comprises at least about 1×
106 units of α
-L-iduronidase activity or at least about 200,000 units/Kg of body weight;(ii) the fusion antibody comprises;
(a) a fusion protein containing the amino acid sequence of an immunoglobulin heavy chain and an α
-L-iduronidase, and (b) an immunoglobulin light chain that comprises a variable region and a constant region;(iii) the fusion antibody binds to an endogenous receptor of a blood brain barrier (BBB) transport system and catalyzes hydrolysis of unsulfated alpha-L-iduronosidic linkages in dermatan sulfate; and (iv) 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 activity compared to an unfused α
-L-iduronidase. - View Dependent Claims (2, 3, 7, 12, 13)
- -L-iduronidase deficiency in the central nervous system of a subject in need thereof, comprising systemically administering to the subject a therapeutically effective dose of a fusion antibody having α
-
4. A method for treating an α
- -L-iduronidase deficiency in the central nervous system of a subject in need thereof, comprising systemically administering to the subject a therapeutically effective dose of a fusion antibody having α
-L-iduronidase activity, wherein;(i) at least about 25,000 units of α
-L-iduronidase activity are delivered to the brain wherein the therapeutically effective dose comprises at least about 1×
106 units of α
-L-iduronidase activity or at least about 200,000 units/Kg of body weight;(ii) the fusion antibody;
comprises;
(a) a fusion protein at least 95% identical to SEQ ID NO;
10, and (b) an immunoglobulin light chain that comprises a variable region and a constant region;(iii) the fusion antibody binds to an extracellular domain of an endogenous receptor of a blood brain barrier (BBB) transport system and catalyzes hydrolysis of unsulfated alpha-L-iduronosidic linkages in dermatan sulfate, wherein the α
-L-iduronidase retains at least 30% activity compared to its activity as a separate entity. - View Dependent Claims (5, 6)
- -L-iduronidase deficiency in the central nervous system of a subject in need thereof, comprising systemically administering to the subject a therapeutically effective dose of a fusion antibody having α
-
8. A method for treating an α
- -L-iduronidase deficiency in the central nervous system of a subject in need thereof, comprising systemically administering to the subject a therapeutically effective dose of a fusion antibody having α
-L-iduronidase activity, wherein;(i) at least about 25,000 units of α
-L-iduronidase activity are delivered to the brain wherein the therapeutically effective dose comprises at least about 1×
106 units of α
-L-iduronidase activity or at least about 200,000 units/Kg of body weight;(ii) the fusion antibody; (a) comprises a heavy chain and a light chain, wherein either the heavy chain or the light chain is fused to an α
-L-iduronidase;(b) binds to the extracellular domain of an endogenous receptor of a blood brain barrier (BBB) transport system; and (c) catalyzes hydrolysis of unsulfated alpha-L-iduronosidic linkages in dermatan sulfate; and (iii) 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 immunoglobulin heavy chain has a variable region and a constant region, wherein the α
-L-iduronidase retains at least 30% activity compared to its activity as a separate entity. - View Dependent Claims (9, 10, 11)
- -L-iduronidase deficiency in the central nervous system of a subject in need thereof, comprising systemically administering to the subject a therapeutically effective dose of a fusion antibody having α
Specification