Therapeutic enzyme fusion protein having a novel structure and use thereof
A fusion protein of a dimeric therapeutic enzyme and an immunoglobulin Fc region, a preparation method thereof, and a composition containing the fusion protein are disclosed.
1. An enzyme fusion protein of the following Formula 1:
wherein X and X′ are the same each other and each independently an enzyme and the enzyme forms a dimer through a non-covalent bond;
L and L′ are the same or different from each other, and are a peptide linker consisting of 10 to 50 amino acid residues;
F is an immunoglobulin Fc region obtained from immunoglobulin G4 (IgG4) and the immunoglobulin Fc region is in a monomer form;
| is a covalent bond; and
: is a non-covalent bond,
wherein the enzyme is selected from the group consisting of beta-glucosidase, alpha-galactosidase, beta-galactosidase, iduronidase, iduronate-2-sulfatase, galactose-6-sulfatase, acid alpha-glucosidase, acid ceramidase, acid sphingomyelinase, galactocerebrosidase, arylsulfatase A, B, beta-hexosaminidase A, B, heparin N-sulfatase, alpha-D-mannosidase, beta-glucuronidase, N-acetylgalactosamine-6 sulfatase, lysosomal acid lipase, alpha-N-acetyl-glucosaminidase, glucocerebrosidase, butyrylcholinesterase, chitinase, glutamate decarboxylase, imiglucerase, lipase, uricase, platelet-activating factor acetylhydrolase, neutral endopeptidase, and myeloperoxidase,
wherein the immunoglobulin Fc region comprises the amino acid sequence of SEQ ID NO: 8, wherein serine at position 2 is substituted with proline; or asparagine at position 71 is substituted with glutamine; or serine at position 2 is substituted with proline and asparagine at position 71 is substituted with glutamine.
2. The enzyme fusion protein of claim 1 , wherein the enzyme X and X′ form a dimer in anti-parallel configuration with each other.
3. The enzyme fusion protein of claim 1 , wherein the enzyme fusion protein has increased stability and reduced binding affinity for lysosome receptors, compared to an enzyme to which an immunoglobulin Fc region is not fused.
4. The enzyme fusion protein of claim 1 , wherein the enzyme is alpha-galactosidase A or beta-galactosidase.
5. The enzyme fusion protein of claim 1 , wherein no chain exchange occurs in the immunoglobulin Fc region.
6. The enzyme fusion protein of claim 1 , wherein the immunoglobulin Fc region is aglycosylated.
7. The enzyme fusion protein of claim 1 , wherein the enzyme comprises the amino acid sequence of SEQ ID NO: 6.
8. The enzyme fusion protein of claim 1 , wherein the enzyme fusion protein comprises the amino acid sequence of SEQ ID NO: 13.