Therapeutic nuclease compositions and methods
Hybrid nuclease molecules and methods for treating an immune-related disease or disorder in a mammal, and a pharmaceutical composition for treating an immune-related disease in a mammal.
1. A method of treating lupus nephritis in a subject comprising administering to the subject a composition comprising: a polypeptide consisting of human RNase 1 operatively coupled with or without a linker to a mutant human IgG1 Fc domain, wherein the Fc domain comprises a P238S mutation and a P331S mutation, numbering according to the EU index, and wherein the Fc domain does not contain a variable region that binds antigen; and a pharmaceutically acceptable carrier.
2. The method of claim 1 , wherein the Fc domain has decreased binding to Fcγ receptors on human cells.
3. The method of claim 1 , wherein the polypeptide has at least 1, 2, 3, 4, or 5-fold less cytotoxicity relative to a polypeptide having wild type Fc domain.
4. The method of claim 1 , wherein the polypeptide has an increased serum half-life relative to a polypeptide comprising human RNase 1 without an Fc domain.
5. The method of claim 1 , wherein the polypeptide degrades circulating RNA and RNA in immune complexes, or inhibits interferon-γ production, or both.
6. The method of claim 1 , wherein the Fc domain comprises a hinge domain, a CH2 domain and a CH3 domain.
7. The method of claim 1 , wherein the Fc domain further comprises a substitution of one or more of three hinge region cysteine residues with serine.
8. The method of claim 1 , wherein the Fc domain further comprises an additional mutation selected from the group consisting of SCC, SSS (residues 220, 226, and 229), G236R, L328R, L234A, and L235A, numbering according to the EU index.
9. The method of claim 1 , wherein the Fc domain further comprises an SCC mutation (residues 220, 226, and 229), numbering according to the EU index.
10. The method of claim 1 , wherein the human RNase 1 is linked to the N-terminus of the Fc domain.
11. The method of claim 1 , wherein the human RNase 1 is linked to the C-terminus of the Fc domain.
12. The method of claim 1 , wherein the human RNase 1 is operatively coupled to the Fc domain without a linker domain.
13. The method of claim 1 , wherein the human RNase 1 is operatively coupled to the Fc domain via a linker domain.
14. The method of claim 13 , wherein the linker domain is a polypeptide linker.
15. The method of claim 14 , wherein the polypeptide linker is a gly-ser linker.
16. The method of claim 1 , wherein the human RNase 1 comprises the amino acid sequence set forth in SEQ ID NO: 101.
17. The method of claim 1 , wherein the Fc domain comprises the amino acid sequence set forth in SEQ ID NO: 90.
18. A method of treating lupus nephritis in a subject comprising administering to the subject a composition comprising: a polypeptide consisting of human RNase 1 operatively coupled without a linker to the N-terminus of a mutant human IgG1 Fc domain, wherein the Fc domain comprises an SCC mutation (residues 220, 226, and 229), a P238S mutation, and a P331S mutation, numbering according to the EU index, and wherein the Fc domain does not contain a variable region that binds antigen; and a pharmaceutically acceptable carrier.
19. The method of claim 18 , wherein the Fc domain comprises a hinge domain, a CH2 domain and a CH3 domain.
20. The method of claim 18 , wherein the human RNase 1 comprises the amino acid sequence set forth in SEQ ID NO: 101.
21. The method of claim 18 , wherein the Fc domain comprises the amino acid sequence set forth in SEQ ID NO: 90.
22. A method of treating lupus nephritis in a subject comprising administering to the subject a composition comprising: a polypeptide consisting of human RNase 1 operatively coupled without a linker to the C-terminus of a mutant human IgG1 Fc domain, wherein the Fc domain comprises an SCC mutation (residues 220, 226, and 229), a P238S mutation, and a P331S mutation, numbering according to the EU index, and wherein the Fc domain does not contain a variable region that binds antigen and a pharmaceutically acceptable carrier.
23. The method of claim 22 , wherein the Fc domain comprises a hinge domain, a CH2 domain and a CH3 domain.
24. The method of claim 22 , wherein the human RNase 1 comprises the amino acid sequence set forth in SEQ ID NO: 101.
25. The method of claim 22 , wherein the Fc domain comprises the amino acid sequence set forth in SEQ ID NO: 90.
26. A method of treating lupus nephritis in a subject, comprising administering to the subject a composition comprising a polypeptide consisting of the amino acid sequence set forth in SEQ ID NO: 96; and a pharmaceutically acceptable carrier.
27. The method of claim 1 , wherein the composition is formulated for intravenous administration.
28. The method of claim 18 , wherein the composition is formulated for intravenous administration.
29. The method of claim 22 , wherein the composition is formulated for intravenous administration.
30. The method of claim 26 , wherein the composition is formulated for intravenous administration.