Fusion proteins comprising sulfoglucosamine sulfohydrolase enzymes and methods thereof
Provided herein are proteins, which are capable of being transported across the blood-brain barrier (BBB) and comprise sulfoglucosamine sulfohydrolase (SGSH) enzyme-Fc fusion polypeptides. Certain embodiments also provide methods of using such proteins to treat Sanfilippo syndrome A.
1. A protein comprising:
a. a first fusion polypeptide comprising a first Fc polypeptide linked to a first N-sulfoglucosamine sulfohydrolase (SGSH) amino acid sequence, wherein the first fusion polypeptide comprises any one of SEQ ID NOs: 65-68; and
b. a second fusion polypeptide comprising a second Fc polypeptide linked to a second SGSH amino acid sequence, wherein the second fusion polypeptide comprises any one of SEQ ID NOs: 93-96.
2. The protein of claim 1 , wherein uptake of the SGSH amino acid sequence into the brain is at least four-fold greater as compared to the uptake of the SGSH enzyme without the modifications to the second Fc polypeptide that result in TfR binding.
3. The protein of claim 1 , wherein the protein does not include an immunoglobulin heavy and/or light chain variable region sequence or an antigen-binding portion thereof.
4. A pharmaceutical composition comprising the protein of claim 1 and a pharmaceutically acceptable excipient.
5. The protein of claim 1 , wherein the first fusion polypeptide comprises SEQ ID NO: 65.
6. The protein of claim 1 , wherein the first fusion polypeptide comprises SEQ ID NO: 66.
7. The protein of claim 1 , wherein the first fusion polypeptide comprises SEQ ID NO: 67.
8. The protein of claim 1 , wherein the first fusion polypeptide comprises SEQ ID NO: 68.
9. The protein of claim 1 , wherein the second fusion polypeptide comprises SEQ ID NO: 93.
10. The protein of claim 1 , wherein the second fusion polypeptide comprises SEQ ID NO: 94.
11. The protein of claim 1 , wherein the second fusion polypeptide comprises SEQ ID NO: 95.
12. The protein of claim 1 , wherein the second fusion polypeptide comprises SEQ ID NO: 96.
13. The protein of claim 1 , wherein the first fusion polypeptide comprises SEQ ID NO: 67 or 68; and the second fusion polypeptide comprises SEQ ID NO:95 or 96.
14. The protein of claim 1 , wherein the first fusion polypeptide is SEQ ID NO: 67 or 68; and the second fusion polypeptide is SEQ ID NO:95 or 96.
15. The protein of claim 1 , wherein the first fusion polypeptide comprises SEQ ID NO: 67; and the second fusion polypeptide comprises SEQ ID NO:95.
16. The protein of claim 1 , wherein the first fusion polypeptide is SEQ ID NO: 67;
and the second fusion polypeptide is SEQ ID NO:95.
17. The protein of claim 1 , wherein the first fusion polypeptide comprises SEQ ID NO: 67; and the second fusion polypeptide comprises SEQ ID NO:96.
18. The protein of claim 1 , wherein the first fusion polypeptide is SEQ ID NO: 67;
and the second fusion polypeptide is SEQ ID NO:96.
19. The protein of claim 1 , wherein the first fusion polypeptide comprises SEQ ID NO: 68; and the second fusion polypeptide comprises SEQ ID NO:95.
20. The protein of claim 1 , wherein the first fusion polypeptide is SEQ ID NO: 68;
and the second fusion polypeptide is SEQ ID NO:95.
21. The protein of claim 1 , wherein the first fusion polypeptide comprises SEQ ID NO: 68; and the second fusion polypeptide comprises SEQ ID NO:96.
22. The protein of claim 1 , wherein the first fusion polypeptide is SEQ ID NO: 68;
and the second fusion polypeptide is SEQ ID NO:96.
23. A pharmaceutical composition comprising the protein of claim 15 and a pharmaceutically acceptable excipient.
24. A pharmaceutical composition comprising the protein of claim 16 and a pharmaceutically acceptable excipient.
25. A pharmaceutical composition comprising the protein of claim 17 and a pharmaceutically acceptable excipient.
26. A pharmaceutical composition comprising the protein of claim 18 and a pharmaceutically acceptable excipient.
27. A pharmaceutical composition comprising the protein of claim 19 and a pharmaceutically acceptable excipient.
28. A pharmaceutical composition comprising the protein of claim 20 and a pharmaceutically acceptable excipient.
29. A pharmaceutical composition comprising the protein of claim 21 and a pharmaceutically acceptable excipient.
30. A pharmaceutical composition comprising the protein of claim 22 and a pharmaceutically acceptable excipient.
31. The protein of claim 1 , which consists of the first fusion polypeptide and the second fusion polypeptide.
32. The protein of claim 31 , wherein the first fusion polypeptide is SEQ ID NO: 67 ; and the second fusion polypeptide is SEQ ID NO:95.
33. The protein of claim 31 , wherein the first fusion polypeptide is SEQ ID NO: 67 ; and the second fusion polypeptide is SEQ ID NO:96.
34. The protein of claim 31 , wherein the first fusion polypeptide is SEQ ID NO: 68 ; and the second fusion polypeptide is SEQ ID NO:95.
35. The protein of claim 31 , wherein the first fusion polypeptide is SEQ ID NO: 68; and the second fusion polypeptide is SEQ ID NO:96.
36. A pharmaceutical composition comprising the protein of claim 32 and a pharmaceutically acceptable excipient.
37. A pharmaceutical composition comprising the protein of claim 33 and a pharmaceutically acceptable excipient.
38. A pharmaceutical composition comprising the protein of claim 34 and a pharmaceutically acceptable excipient.
39. A pharmaceutical composition comprising the protein of claim 35 and a pharmaceutically acceptable excipient.