Methods and compositions for increasing α-L-iduronidase activity in the CNS
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.
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.
2. The method of claim 1 , wherein the endogenous receptor of a blood brain barrier (BBB) transport system is an insulin receptor, transferrin receptor, IGF receptor, or leptin receptor.
3. The method of claim 1 , wherein the endogenous receptor of a blood brain barrier (BBB) transport system is an insulin receptor.
4. The method of claim 1 , wherein the endogenous receptor of a blood brain barrier (BBB) transport system is a human insulin receptor.
5. The method of claim 1 , wherein the subject is a human subject.
6. The method of claim 1 , wherein the IDUA specific activity of the fusion antibody is at least 200,000 units/mg.
7. The method of claim 1 , wherein the systemic administration is parenteral, intravenous, subcutaneous, intramuscular, trans-nasal, intra-arterial, transdermal, or respiratory.
8. The method of claim 1 , wherein the systemic administration is intravenous.
9. The method of claim 1 , wherein the delivery occurs within two hours or less after systemic administration.
10. The method of claim 1 , wherein the fusion protein is at least 95% identical to SEQ ID NO:10.
11. The method of claim 1 , wherein the fusion protein comprises SEQ ID NO:10.
12. The method of claim 1 , wherein the α-L-iduronidase retains at least 40% of its enzymatic activity compared to an unfused α-L-iduronidase.
13. The method of claim 1 , wherein the therapeutically effective dose comprises at least about 300,000 units of α-L-iduronidase activity/Kg of body weight.
14. The method of claim 1 , wherein the fusion antibody having α-L-iduronidase activity is a single chain antibody.
15. The method of claim 1 , wherein the fusion antibody having α-L-iduronidase activity is a single chain Fv (scFv) antibody.
16. The method of claim 1 , wherein the fusion antibody having α-L-iduronidase activity is a monoclonal antibody.
17. The method of claim 1 , wherein the fusion antibody having α-L-iduronidase activity further comprises an immunoglobulin light chain.
18. The method of claim 1 , wherein the fusion antibody further comprises a Fab region that binds to an endogenous receptor of a brain cell membrane (BCM) transport system.
19. The method of claim 1 , wherein the therapeutically effective dose has no detectable aggregates.
20. The method of claim 1 , wherein the therapeutically effective dose comprises polysorbate.
21. The method of claim 1 , wherein the therapeutically effective dose comprises polysorbate at a concentration of 0.01-1%.
22. The method of claim 1 , wherein the therapeutically effective dose comprises polysorbate-80.
23. The method of claim 1 , wherein the therapeutically effective dose comprises polysorbate-80 at a concentration of 0.01-1%.
24. The method of claim 1 , wherein the fusion protein having α-L-iduronidase activity catalyzes hydrolysis of unsulfated alpha-L-iduronosidic linkages in dermatan sulfate.
25. The method of claim 1 , wherein the fusion protein having α-L-iduronidase activity catalyzes hydrolysis of unsulfated alpha-L-iduronosidic linkages in heparan sulfate.
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.
27. The method of claim 26 , wherein the fusion antibody further comprises an immunoglobulin heavy chain.
28. The method of claim 26 , wherein the therapeutically effective dose comprises polysorbate.
29. The method of claim 26 , wherein the therapeutically effective dose comprises polysorbate at a concentration of 0.01-1%.
30. The method of claim 26 , wherein the therapeutically effective dose comprises polysorbate-80.
31. The method of claim 26 , wherein the therapeutically effective dose comprises polysorbate-80 at a concentration of 0.01-1%.