Soluble hybrid Fcγ receptors and related methods
Inventors
Birks, Carl W. • Fox, Brian A. • Rixon, Mark W. • Ellsworth, Jeff L.
Assignees
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Publication Number
US-10570187-B2
Publication Date
2020-02-25
Expiration Date
Abstract
Disclosed are soluble hybrid Fcγ receptor (FcγR) polypeptide compositions and related methods of using such polypeptides to treat IgG-mediated and immune complex-mediated inflammation. Also disclosed are related compositions and methods for producing the soluble hybrid FcγR polypeptides.
Core Innovation
Soluble hybrid Fcγ receptor therapeutics are disclosed for treating IgG- and immune-complex-mediated inflammation. The invention is centered on soluble hybrid FcγR polypeptides that specifically bind the Fc region of IgG, including human IgG1, and are provided as extracellular Ig-domain constructs.
The therapeutic receptors are described in terms of hybrid FcγR design in which specified extracellular Ig-domain regions are used, including substitutions within FcγRIA D1 using FcγRIIA, FcγRIIB, FcγRIIIA, and FcγRIIIB Ig domains. This design supports specific IgG Fc binding with high affinity and is linked to blocking immune-complex binding and signaling.
The disclosure further provides isolated nucleic acids and expression vectors encoding the soluble hybrid FcγRs, including embodiments with secretory signal sequences. It also describes cultured-cell embodiments for producing and secreting the soluble hybrid Fcγ receptors and for producing and recovering the secreted receptors. Therapeutic use is described in immune diseases and inflammatory conditions involving IgG or immune complexes.
Claims Coverage
The independent claim coverage centers on an isolated nucleic acid encoding a specified IgG-Fc-binding polypeptide, with six inventive features across the independent claim and dependents.
Isolated nucleic acid encoding an Fc region-binding polypeptide
An isolated nucleic acid molecule encodes a polypeptide selected from amino acid residues 43-310 of SEQ ID NO:42, amino acid residues 21-286 of SEQ ID NO:44, or amino acid residues 21-286 of SEQ ID NO:46, wherein the polypeptide specifically binds the Fc region of IgG.
Expression vector with promoter and transcription terminator
An expression vector comprises, in operable linkage, a transcription promoter, the nucleic acid molecule encoding the Fc region-binding polypeptide, and a transcription terminator.
Expression vector nucleic acid with defined nucleotide ranges
The expression vector nucleic acid molecule contains one of defined nucleotide ranges taken from specified SEQ ID NO sequences.
Expression vector including a secretory signal sequence
The expression vector includes an additional secretory signal sequence.
Cultured cell expressing and secreting the encoded polypeptide
A cultured cell contains an expression vector such that the cell expresses and secretes the resulting polypeptide encoded by a DNA segment.
Method producing secreted polypeptide by culturing and recovering
A method produces the polypeptide by culturing a cell containing an introduced expression vector so the cell expresses the encoded polypeptide, secretes it from the cell, and recovers the secreted polypeptide.
The claim set focuses on nucleic acids encoding specific IgG-Fc-binding polypeptides, and on their use in expression vectors and cultured cells to achieve secretion and recovery of the encoded polypeptide.
Stated Advantages
Treats IgG- and immune-complex-mediated inflammation.
Blocks immune-complex binding/signaling effects and reduces inflammation.
Reduces disease incidence and progression in collagen antibody-induced arthritis and related inflammatory settings.
Reduces paw inflammation scores and edema.
Reduces neutrophil infiltration.
Modulates immune mediators including IL-6 and anti-type II collagen antibodies.
Inhibits immune complex precipitation and reduces mast-cell cytokines.
Blocks complement-mediated lysis.
Reduces temperature-dependent self-aggregation and improves IgG-resin recovery compared with native soluble FcγRIA.
Provides in vivo anti-inflammatory effects in reverse passive Arthus reactions.
Documented Applications
Immune diseases involving autoimmune/inflammatory conditions mediated by IgG or immune complexes.
Arthus reaction and inhibition of immune-complex precipitation, cytokine secretion, edema, and neutrophil infiltration.
Suppression in collagen antibody-induced arthritis model and collagen-induced arthritis model.
Use in collagen antibody-induced arthritis (CIA) and related inflammatory immune-complex settings.
Use in reverse passive Arthus reactions for anti-inflammatory effects.
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