Methods and compositions for increasing arylsulfatase A activity in the CNS
Provided herein are methods and compositions for treating a subject suffering from a deficiency in arylsulfatase A in the CNS. The methods include systemic administration of a bifunctional fusion antibody comprising an antibody to a human insulin receptor and an arylsulfatase A.
1. A fusion antibody comprising:
(a) an amino acid sequences of an immunoglobulin heavy chain; and
(b) a fusion protein comprising an amino acid sequence of an arylsulfatase A monomer covalently linked to the amino acid sequence of an immunoglobulin light chain,
wherein the immunoglobulin light chain is an immunoglobulin light chain of kappa or lambda class and comprises a CDR1 corresponding to the amino acid sequence of SEQ ID NO:4, a CDR2 corresponding to the amino acid sequence of SEQ ID NO:5, or a CDR3 corresponding to the amino acid sequence of SEQ ID NO:6; wherein the fusion antibody crosses the blood brain barrier (BBB) and catalyzes hydrolysis of 2-sulfate groups of cerebroside sulfate esters and sulfatide sphingolipids, and wherein the arylsulfatase A monomer retains at least 20% of its activity compared to its activity as a separate entity.
2. The fusion antibody of claim 1 , wherein the amino acid sequence of the arylsulfatase A monomer is covalently linked to the carboxy terminus of the amino acid sequence of the immunoglobulin light chain.
3. The fusion antibody of claim 1 , wherein the immunoglobulin heavy chain is an immunoglobulin heavy chain of IgG.
4. The fusion antibody of claim 1 , wherein the fusion antibody crosses the BBB by binding an endogenous BBB receptor-mediated transport system.
5. The fusion antibody of claim 1 , wherein the fusion antibody crosses the BBB via the insulin receptor.
6. The fusion antibody of claim 1 , wherein the fusion antibody crosses the BBB by binding a human insulin receptor.
7. A method for treating an arylsulfatase A (ASA) 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 arylsulfatase A activity, wherein the fusion antibody comprises:
(a) an amino acid sequence of an immunoglobulin heavy chain; and
(b) a fusion protein comprising an amino acid sequence of an arylsulfatase A monomer covalently linked to an amino acid sequence of an immunoglobulin light chain,
wherein the immunoglobulin light chain is an immunoglobulin light chain of kappa or lambda class and comprises a CDR1 corresponding to the amino acid sequence of SEQ ID NO:4, a CDR2 corresponding to the amino acid sequence of SEQ ID NO:5, or a CDR3 corresponding to the amino acid sequence of SEQ ID NO:6; wherein the fusion antibody crosses the blood brain barrier (BBB), and wherein the arylsulfatase A monomer retains at least 20% of its activity compared to its activity as a separate entity.
8. The method of claim 7 , wherein the amino acid sequence of the arylsulfatase is covalently linked to the carboxy terminus of the amino acid sequence of the immunoglobulin light chain.
9. The method of claim 7 , wherein the fusion antibody is post-translationally modified by a sulfatase modifying factor type 1 (SUMF1).
10. The method of claim 7 , wherein the fusion antibody comprises formylglycine.
11. The method of claim 7 , wherein the fusion antibody catalyzes hydrolysis of cerebroside sulfate esters and sulfatide sphingolipids.
12. The method of claim 7 , wherein the immunoglobulin heavy chain is an immunoglobulin heavy chain of IgG.
13. The method of claim 7 , wherein the fusion antibody crosses the BBB by binding an endogenous BBB receptor-mediated transport system.
14. The method of claim 7 , wherein the fusion antibody crosses the BBB via the insulin receptor.
15. The method of claim 7 , wherein the fusion antibody crosses the BBB by binding a human insulin receptor.
16. The method of claim 7 , wherein the systemic administration is parenteral, intravenous, subcutaneous, intra-muscular, trans-nasal, intra-arterial, transdermal, or respiratory.