Methods and compositions for increasing arylsulfatase A activity in the CNS
View Patent ↗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 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) a fusion protein comprising the amino acid sequences of an immunoglobulin heavy chain and an arylsulfatase A monomer; and (b) an immunoglobulin light chain; wherein the fusion antibody crosses the blood brain barrier (BBB) and the ASA retains at least 20% of its activity, on a molar basis, compared to its activity as a separate entity.
2. The method of claim 1 , wherein the amino acid sequence of the arylsulfatase A is covalently linked to the carboxy terminus of the amino acid sequence of the immunoglobulin heavy chain.
3. The method of claim 1 , wherein the fusion antibody is post-translationally modified by a sulfatase modifying factor type 1 (SUMF1).
4. The method of claim 1 , wherein the fusion antibody comprises formylglycine.
5. The method of claim 1 , wherein the fusion antibody catalyzes hydrolysis of cerebroside sulfate esters and sulfatide sphingolipids.
6. The method of claim 1 , wherein the ASA and the immunoglobulin each retains at least 20% of its activity, on a molar basis, compared to its activity as a separate entity.
7. The method of claim 1 , wherein at least about 100 ug of arylsulfatase A enzyme are delivered to the brain, normalized per 50 kg body weight.
8. The method of claim 1 , wherein the therapeutically effective dose comprises at least about 10 units/Kg of body weight.
9. The method of claim 1 , wherein the arylsulfatase A specific activity of the fusion antibody is at least 10 units/mg of protein.
10. The method of claim 1 , wherein the immunoglobulin heavy chain is an immunoglobulin heavy chain of IgG.
11. The method of claim 1 , wherein the immunoglobulin heavy chain comprises a CDR1 corresponding to the amino acid sequence of SEQ ID NO:1, a CDR2 corresponding to the amino acid sequence of SEQ ID NO:2, or a CDR3 corresponding to the amino acid sequence of SEQ ID NO:3.
12. The method of claim 1 , wherein the immunoglobulin light chain is an immunoglobulin light chain of kappa or lambda class.
13. The method of claim 1 , wherein the immunoglobulin light chain 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.
14. The method of claim 1 , wherein the fusion protein comprising the amino acid sequences of an immunoglobulin heavy chain and an arylsulfatase A comprises an amino acid sequence that is at least 80% identical to SEQ ID NO:10.
15. The method of claim 1 , wherein the fusion antibody crosses the BBB by binding an endogenous BBB receptor-mediated transport system.
16. The method of claim 1 , wherein the fusion antibody crosses the BBB via an endogenous BBB receptor selected from the group consisting of the insulin receptor, transferrin receptor, leptin receptor, lipoprotein receptor, and the insulin-like growth factor (IGF) receptor.
17. The method of claim 1 , wherein the fusion antibody crosses the BBB by binding an insulin receptor.
18. The method of claim 1 , wherein the systemic administration is parenteral, intravenous, subcutaneous, intra-muscular, trans-nasal, intra-arterial, transdermal, or respiratory.
19. The method of claim 1 , wherein the arylsulfatase A (ASA) deficiency in the central nervous system is metachromatic leukodystrophy (MLD).