Diagnosing and treating IGA nephropathy
Inventors
Suzuki, Hitoshi • Fan, Run • Julian, Bruce A. • Novak, Jan • Moldoveanu, Zina • Zhang, Zhixin • Tomana, Milan • Mestecky, Jiri • Wyatt, Robert J. • Tomino, Yasuhiko • Suzuki, Yusuke • Olson, Stephen • Renfrow, Matthew B.
Assignees
Juntendo University School of Medicine • UAB Research Foundation • University of Tennessee Research Foundation • Walter Reed Army Institute of Research
Publication Number
US-9655963-B2
Publication Date
2017-05-23
Expiration Date
2030-05-26
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Abstract
Provided are methods of diagnosing IgA nephropathy in a subject. Optionally, the methods comprise isolating an IgG from the subject and determining whether the IgG binds to a galactose-deficient IgA1. Optionally, the methods comprise providing a biological sample from the subject and detecting in the sample a mutation in a IGH gene, wherein the mutation is in a nucleotide sequence encoding a complementarity determining region 3 (CDR3) of a IGH variable region. Optionally, the methods comprise determining a level of IgG specific for a galactose-deficient IgA1 in the subject. Also provided are methods of treating or reducing the risk of developing IgA nephropathy in a subject.
Core Innovation
IgA nephropathy (IgAN), also called Berger disease, is characterized by the deposition of IgA- and IgG-containing immune complexes in the glomerular mesangium of the kidney. The IgA involved is exclusively of the IgA1 subclass and aberrantly glycosylated, specifically deficient in galactose (Gal) in the hinge-region O-linked glycans. This aberrant glycosylation leads to formation of immune complexes that bind mesangial cells, inducing renal manifestations characteristic of IgAN. However, the events initiating the disease appear to be extra-renal, as evidenced by the recurrence of IgAN after kidney transplantation.
The invention provides methods for diagnosing IgA nephropathy by isolating IgG from a subject and determining whether this IgG binds to galactose-deficient IgA1. Binding indicates the subject has or is at risk of developing IgAN. Additionally, the methods involve detecting mutations in IGH genes encoding the complementarity determining region 3 (CDR3) of the IGH variable region, with certain mutations indicative of disease risk. Furthermore, measuring levels of IgG specific for galactose-deficient IgA1, and optionally galactose-deficient IgA1 itself, aids diagnosis and assessment of disease progression.
Also provided are methods of treatment comprising administering agents that inhibit binding of IgG to galactose-deficient IgA1 or reduce levels of specific IgG. Therapeutic agents can be small molecules, polypeptides, inhibitory nucleic acid molecules, or peptidomimetics. Isolated antibodies or fragments specific to galactose-deficient hinge-region O-glycans of IgA1, particularly those with alanine to serine substitutions in CDR3, are described. Passive animal models of IgAN are generated by injecting immune complexes of galactose-deficient IgA1 and specific IgG, facilitating study and treatment development.
Claims Coverage
The claims of the patent include one independent claim focusing on a method of treating IgA nephropathy based on diagnostic measurement and subsequent treatment steps.
Diagnostic measurement of specific IgG, IgA1, and galactose-deficient IgA1 levels
A method involving obtaining a biological sample from a subject, determining levels of IgG, IgA1, or both specific for the hinge region of galactose-deficient IgA1, and determining the level of galactose-deficient IgA1 in the sample. Increased levels compared to controls indicate disease or risk.
Use of antibodies specific for galactose-deficient hinge-region O-linked glycans
Detection of galactose-deficient IgA1 in the sample utilizes an antibody specific for galactose-deficient hinge-region O-linked glycan of IgA1.
Treatment of IgA nephropathy upon detection
Performing treatment of IgA nephropathy following diagnostic determination.
Isolation of IgG and IgA1 from B cells
Isolation of IgG, IgA1, or both from B cells within the biological sample, including isolation from peripheral blood mononuclear cells, optionally immortalized by Epstein-Barr virus transformation.
Monoclonal antibody utilization
Employment of monoclonal antibodies specific for galactose-deficient hinge-region O-linked glycans.
Presence of alanine to serine substitution in CDR3
Identification that the IgG, IgA1, or both specific for the hinge region of galactose-deficient IgA1 comprise an alanine to serine amino acid substitution in the complementarity determining region 3 (CDR3) of an immunoglobulin heavy chain variable region.
The claimed method covers diagnostic determination based on specific immunoglobulin and galactose-deficient IgA1 levels, the use of specific antibodies, isolation methods of immunoglobulins from B cells, characterization of amino acid substitutions, and therapeutic treatment following diagnosis.
Stated Advantages
The diagnostic methods provide high sensitivity and specificity for detecting IgA nephropathy or risk thereof.
Levels of IgG specific for galactose-deficient IgA1 correlate with disease progression markers like proteinuria and urinary immune complexes.
Blocking IgG binding to galactose-deficient IgA1 may reduce formation of pathogenic immune complexes, preventing renal injury.
Animal models injected with immune complexes reproduce IgAN pathology, enabling further study and therapeutic testing.
Monovalent antibody fragments or synthetic glycopeptides can inhibit pathogenic immune complex formation, providing novel therapeutic approaches.
Documented Applications
Diagnosing IgA nephropathy in subjects by measuring specific IgG and galactose-deficient IgA1 levels.
Treating or reducing risk of developing IgA nephropathy via administration of agents inhibiting IgG binding to galactose-deficient IgA1 or reducing IgG levels.
Use of isolated antibodies or fragments specific for galactose-deficient hinge-region O-linked glycans of IgA1 in diagnostic assays.
Creating animal models of IgA nephropathy by injecting immune complexes comprising galactose-deficient IgA1 and specific IgG.
Immunoassays and kits comprising galactose-deficient IgA1 and antibodies specific to galactose-deficient IgA1 for research and diagnostic use.
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