Antibody fusion proteins with a modified FcRn binding site
Disclosed are antibody fusion proteins with a modified FcRn binding site and nucleic acid molecules encoding them. The antibody fusion protein include two polypeptide chains, wherein the first polypeptide chain includes a biologically active molecule linked to at least a portion of an immunoglobulin constant region. The second polypeptide chain includes at least a portion of an immunoglobulin constant region. One of the polypeptide chains includes a mutation in the FcRn binding site that reduces binding to FcRn. Also disclosed are methods of producing the fusion proteins and methods of using the fusion proteins for treating diseases and conditions alleviated by the administration of the fusion proteins.
1. A protein comprising two polypeptide chains, wherein the first polypeptide chain comprises native mature human interferon-β and at least a portion of an IgG constant region, the second polypeptide chain comprises at least a portion of an IgG constant region, and one of the polypeptide chains comprises a substitution corresponding to position 435 in the IgG FcRn binding site, wherein the substitution is H435A.
2. The protein of claim 1 , wherein the human interferon-β is linked to the amino-terminus of the immunoglobulin constant region.
3. The protein of claim 1 , wherein the human interferon-β is linked to the carboxy-terminus of the immunoglobulin constant region.
4. The protein of claim 1 , wherein the second polypeptide chain comprises a biologically active molecule.
5. The protein of claim 1 , wherein at least the first or second polypeptide chain comprises an antibody variable domain.
6. The protein of claim 1 , wherein the portion of the IgG is an Fc fragment.
7. The protein of claim 1 , wherein the IgG is IgG1, IgG2, IgG3, or IgG4.
8. A protein comprising two polypeptide chains, wherein the first polypeptide chain comprises wild-type native mature human interferon-β having one or more mutations selected from the group consisting of C17S, C17A, C17V, C17M, F50H, L57A, L130A, H131A, K136A, H140A, and H140T and at least a portion of an IgG constant region, the second polypeptide chain comprises at least a portion of an IgG constant region, and one of the polypeptide chains comprises a substitution corresponding to position 435 in the IgG FcRn binding site, wherein the substitution is H435A.
9. A pharmaceutical composition comprising the protein of claim 1 and a pharmaceutically acceptable carrier.