Abstract
IgA nephropathy (IgAN) is the most common primary glomerulonephritis and an important cause of kidney failure.
It is a mesangioproliferative glomerular disease defined by characteristic IgA1 mesangial deposits. These
mesangial deposits likely originate from circulating immune complexes that contain IgA1 with Galactose (Gal)-
deficient O-glycans (Gd-IgA1, the autoantigen) that are bound by IgG autoantibodies. The pathogenesis model
describing IgAN as an autoimmune disease was based on the discovery of IgG autoantibodies that bind Gd-
IgA1 in the laboratory of Dr. Jan Novak at the University of Alabama at Birmingham (UAB). As part of these
studies, Dr. Novak’s laboratory developed assays for the detection and quantitative assessment of both Gd-IgA1
and IgG autoantibodies. The use of these assays for analysis of serum samples from several cohorts of IgAN
patients has been published; both the Gd-IgA1 assay and the IgG autoantibody assay have potential as markers
for preclinical detection of IgAN, prediction of outcome, and monitoring the response to therapy. The established
pathogenesis model of IgAN enabled pharmaceutical industry to start developing and testing treatment for the
disease. However, only secondary markers (e.g., proteinuria and estimated glomerular filtration rate [eGFR]) are
currently used as the endpoints, adding to the time and cost of clinical trials. Thus, clinical-grade tests that assess
primary causative markers are urgently needed. We have previously developed an IgAN-specific biomarker
assay for the IgG autoantibody. However, to date, there still does not exist a clinical-grade test for the robust
measurement of Gd-IgA1 (the autoantigen) despite it being considered a key biomarker for the disease. To
address this requisite, Reliant Glycosciences has developed a clinical-grade version of a N-acetylgalactosamine
(GalNAc)-specific lectin-based Gd-IgA1 assay that detects terminal GalNAc (i.e., Galactose-deficient) O-glycans
on IgA1 in serum. This assay is based on the original Novak assay that was part of foundational studies in IgAN
that defined the pathogenesis of the disease. We have a fully developed proof of concept assay kit that has
shown promising performance in terms of sensitivity and reproducibility in both internal and external studies with
a set of performance quality control samples. Thus, this proposal is being submitted as a straight-to Phase II
application. The goal of this proposal is to expand our validation studies, begin prototype production, and start
the regulatory approval process for this Gd-IgA1 assay kit (called the GalD Assay). We will also establish the
assay in a CLIA setting so that it can be validated and commercialized for clinical use.
