METHODS AND COMPOSITIONS FOR INCREASING ALPHA-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 0.5% of the therapeutically effective dose is delivered to the brain;
(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;
(iii) the fusion antibody binds to an extracellular domain of the human insulin receptor; 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 to the carboxy terminus of the amino acid sequence of the immunoglobulin heavy chain.
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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.
113 Citations
23 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 0.5% of the therapeutically effective dose is delivered to the brain; (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;(iii) the fusion antibody binds to an extracellular domain of the human insulin receptor; 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 to the carboxy terminus of the amino acid sequence of the immunoglobulin heavy chain. - View Dependent Claims (2, 3, 4, 5, 6, 7)
- -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
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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 0.5% of the therapeutically effective dose is delivered to the brain; (ii) the fusion antibody;
comprises;
(a) a fusion protein at least 95% identical to SEQ ID NO;
10, and (b) an immunoglobulin light chain;(iii) the fusion antibody binds to an extracellular domain of the human insulin receptor; and catalyzes hydrolysis of unsulfated alpha-L-iduronosidic linkages in dermatan sulfate. - View Dependent Claims (9, 10, 11, 12, 13, 14)
- -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
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15. 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 0.5% of the therapeutically effective dose is delivered to the brain; (ii) the fusion antibody;
comprises a fusion protein containing the amino acid sequence of an immunoglobulin heavy chain and an α
-L-iduronidase, or a fusion protein containing the amino acid sequence of an immunoglobulin light chain and an α
-L-iduronidase;
binds to the extracellular domain of the human insulin receptor; and
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 to the carboxy terminus of the amino acid sequence of the immunoglobulin heavy chain or the immunoglobulin light chain. - View Dependent Claims (16, 17, 18, 19, 20, 21, 22, 23)
- -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