Therapeutic nuclease compositions and methods
Inventors
Ledbetter, Jeffrey A. • Hayden-Ledbetter, Martha • Elkon, Keith • Sun, Xizhang
Assignees
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Publication Number
US-10202588-B2
Publication Date
2019-02-12
Expiration Date
Abstract
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.
Core Innovation
The invention relates to a polypeptide for treating systemic lupus erythematosus (SLE) and Sjogren's syndrome, and for degrading RNA containing immune complexes in a subject. The polypeptide consists of human RNase 1 operatively coupled with or without a linker to a mutant human IgG1 Fc domain, and the Fc domain does not contain a variable region that binds antigen. The mutant Fc domain comprises P238S and P331S mutations (EU index), and in specific embodiments also comprises an SCC mutation (residues 220, 226, and 229; EU index).
The disclosed constructions include configurations in which human RNase 1 is operatively coupled to either the N-terminus or the C-terminus of the mutant human IgG1 Fc domain, including embodiments with or without a linker. Fc structure is further defined in embodiments by including a hinge domain, a CH2 domain, and a CH3 domain. Sequence identities are provided using SEQ ID NO references for the human RNase 1 and for the mutant human IgG1 Fc domain.
In the described embodiments directed to immune consequences, the polypeptide is used to degrade RNA containing immune complexes and to inhibit interferon-gamma production, and it targets interferon response outcomes associated with lupus-like disease. In the provided experimental characterization, administration is associated with reduced kidney inflammation, including IgG/C3 deposition, PAS inflammation, macrophage infiltration, and reduced glomerular tuft size, together with reduced interferon response gene expression.
Claims Coverage
The independent claims cover methods directed to treating SLE and Sjogren's syndrome and methods directed to degrading RNA containing immune complexes, using engineered human RNase 1–mutant human IgG1 Fc fusion polypeptides or a polypeptide defined by SEQ ID NO: 96. Across the independent claims, the core inventive framework specifies operatively coupled human RNase 1 and a mutant human IgG1 Fc domain lacking an antigen-binding variable region, with defined Fc mutations and specified RNase/Fc coupling architectures.
Treating systemic lupus erythematosus using human RNase 1 operatively coupled with mutant human IgG1 Fc
A method of treating systemic lupus erythematosus (SLE) in a subject comprising administering a composition containing a polypeptide consisting of human RNase 1 operatively coupled with or without a linker to a mutant human IgG1 Fc domain comprising P238S and P331S mutations (EU index), and not containing a variable region that binds antigen, together with a pharmaceutically acceptable carrier.
Treating SLE using RNase 1 operatively coupled without a linker to the N-terminus Fc with SCC/P238S/P331S
A method of treating SLE in a subject comprising administering a composition containing a polypeptide consisting of human RNase 1 operatively coupled without a linker to the N-terminus of a mutant human IgG1 Fc domain comprising an SCC mutation (residues 220, 226, and 229), P238S, and P331S mutations (EU index), and not containing a variable region that binds antigen, together with a pharmaceutically acceptable carrier.
Treating SLE using RNase 1 operatively coupled without a linker to the C-terminus Fc with SCC/P238S/P331S
A method of treating SLE in a subject comprising administering a composition containing a polypeptide consisting of human RNase 1 operatively coupled without a linker to the C-terminus of a mutant human IgG1 Fc domain comprising an SCC mutation (residues 220, 226, and 229), P238S, and P331S mutations (EU index), and not containing a variable region that binds antigen, together with a pharmaceutically acceptable carrier.
Degrading RNA containing immune complexes using human RNase 1–mutant IgG1 Fc with P238S/P331S
A method of degrading RNA containing immune complexes in a subject comprising administering a composition containing a polypeptide consisting of human RNase 1 operatively coupled with or without a linker to a mutant human IgG1 Fc domain comprising P238S and P331S mutations (EU index), and not containing a variable region that binds antigen, together with a pharmaceutically acceptable carrier.
Degrading RNA containing immune complexes using a polypeptide of SEQ ID NO: 96
A method of degrading RNA containing immune complexes in a subject comprising administering a composition containing a polypeptide consisting of the amino acid sequence set forth in SEQ ID NO: 96, and a pharmaceutically acceptable carrier.
Degrading RNA containing immune complexes using RNase 1 operatively coupled without a linker to the N-terminus Fc with SCC/P238S/P331S
A method of degrading RNA containing immune complexes in a subject comprising administering a composition containing a polypeptide consisting of human RNase 1 operatively coupled without a linker to the N-terminus of a mutant human IgG1 Fc domain comprising an SCC mutation (residues 220, 226, and 229), P238S, and P331S mutations (EU index), and not containing a variable region that binds antigen, together with a pharmaceutically acceptable carrier.
Treating Sjogren’s syndrome using a polypeptide of SEQ ID NO: 96
A method of treating Sjogren's syndrome in a subject comprising administering a composition containing a polypeptide consisting of the amino acid sequence set forth in SEQ ID NO: 96, and a pharmaceutically acceptable carrier.
Treating Sjogren’s syndrome using human RNase 1 operatively coupled with mutant IgG1 Fc with P238S/P331S
A method of treating Sjogren's syndrome in a subject comprising administering a composition containing a polypeptide consisting of human RNase 1 operatively coupled with or without a linker to a mutant human IgG1 Fc domain comprising P238S and P331S mutations (EU index), and not containing a variable region that binds antigen, together with a pharmaceutically acceptable carrier.
Treating Sjogren’s syndrome using RNase 1 operatively coupled without a linker to the N-terminus Fc with SCC/P238S/P331S
A method of treating Sjogren's syndrome in a subject comprising administering a composition containing a polypeptide consisting of human RNase 1 operatively coupled without a linker to the N-terminus of a mutant human IgG1 Fc domain comprising an SCC mutation (residues 220, 226, and 229), P238S, and P331S mutations (EU index), and not containing a variable region that binds antigen, together with a pharmaceutically acceptable carrier.
Treating Sjogren’s syndrome using RNase 1 operatively coupled without a linker to the C-terminus Fc with SCC/P238S/P331S
A method of treating Sjogren's syndrome in a subject comprising administering a composition containing a polypeptide consisting of human RNase 1 operatively coupled without a linker to the C-terminus of a mutant human IgG1 Fc domain comprising an SCC mutation (residues 220, 226, and 229), P238S, and P331S mutations (EU index), and not containing a variable region that binds antigen, together with a pharmaceutically acceptable carrier.
Across the independent claims, the inventive coverage is centered on administering engineered human RNase 1–mutant human IgG1 Fc fusion polypeptides, or a polypeptide defined by SEQ ID NO: 96, to treat SLE and Sjogren's syndrome and to degrade RNA containing immune complexes. The claim framework includes defined Fc point mutations (P238S and P331S, and in specific embodiments SCC at EU residues 220/226/229), excludes an antigen-binding variable region in the Fc, and specifies operatively coupled architectures including N-terminus versus C-terminus coupling and optional or absent linker.
Stated Advantages
Reduced cytotoxicity relative to a polypeptide having a wild-type Fc domain.
Decreased binding to Fcγ receptors on human cells.
Increased serum half-life compared with a human RNase 1 polypeptide lacking an Fc domain.
Degradation of circulating RNA and/or RNA in immune complexes.
Inhibition of interferon-gamma production.
Reduced kidney inflammation, including IgG/C3 deposition, PAS inflammation, macrophage infiltration, and reduced glomerular tuft size.
Reduced interferon response gene expression in spleens, including reduced IRF7 and some other IRGs.
In vitro inhibition of interferon-alpha production/activity associated with lupus immune complexes.
In vivo reduction of interferon-stimulated genes (ISG expression) associated with poly(I:C)-induced effects.
Documented Applications
Treating systemic lupus erythematosus (SLE) in a subject by administering a hybrid RNase 1–mutant human IgG1 Fc composition.
Treating Sjogren's syndrome in a subject by administering a composition comprising the polypeptide sequence set forth in SEQ ID NO: 96.
Treating Sjogren's syndrome in a subject by administering a hybrid RNase 1–mutant human IgG1 Fc composition.
Degrading RNA containing immune complexes in a subject by administering a composition comprising the polypeptide sequence set forth in SEQ ID NO: 96.
Degrading RNA containing immune complexes in a subject by administering a hybrid RNase 1–mutant human IgG1 Fc composition.
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