# Pathogenic Autoantibodies with Specificity for Aberrant Glycoproteins: Assessment of a Therapeutic Target in an Autoimmune Disease

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $515,750

## Abstract

IgA nephropathy (IgAN), the most common glomerulonephritis worldwide, leads to end-stage renal disease in
20-40% of patients and can reduce life expectancy by up to 10 years, as there is no known cure or disease-
specific treatment. Most IgAN patients, regardless of age and ethnicity, have immunologic defects resulting in
generation of pathogenic IgA1-containing immune complexes, which ultimately deposit in the kidneys to induce
renal injury. These renal immunodeposits likely originate from circulating immune complexes consisting of IgA1
with hinge-region galactose-deficient O-glycans (Gd-IgA1) bound by Gd-IgA1-specific IgG autoantibodies. The
long-term goal of this project is to define the underlying mechanisms that lead to the formation of pathogenic
immune complexes, so that IgAN-specific treatments can be developed. Our hypothesis is that a molecular-
level characterization of Gd-IgA1-specific IgG autoantibodies from IgAN patients coupled with an atomic-level
characterization of autoantibodies in immune complexes will significantly advance our understanding of
immune-complex formation in IgAN. This information will in-turn provide a basis for development of new
disease-specific treatments. Over the past three years, the laboratories of the investigators have utilized
biochemical, molecular, structural, and clinical studies to begin characterization of IgAN-specific
autoantibodies. We have shown that IgG autoantibodies from patients with IgAN harbor a sequence (amino
acids YCSR/K) at the junction of framework 3 and the CDR3 in the variable part of the heavy chain (VH),
wherein the serine residue is essential for Gd-IgA1 binding. This serine residue originates from a somatic
hypermutation (Ala->Ser) and not from a genetic mutation of a VH germline gene. Our crystallographic studies
with an IgAN-derived (YCSK) and a germline-reverted (YCAK) recombinant IgG autoantibody revealed that
this seemingly minor difference in the amino-acid sequence had allosteric effects on elements surrounding the
serine residue, generating a new surface juxtaposed to the CDR loops. This surface is a potential binding site
for part of the Gd-IgA1 hinge-region glycopeptide and is a potential target for the design of IgG autoantibody
inhibitors. In this proposal, we will determine the population- and individual-level variability of IgG
autoantibodies in IgAN based on VH/VL sequences and Gd-IgA1 binding (Aim 1), determine the structural
features of representative IgG autoantibodies and the molecular mechanism of Gd-IgA1 recognition (Aim 2),
and develop approaches to block the binding of IgG autoantibodies to Gd-IgA1 (Aim 3). By leveraging our
access to biobanked clinical samples, new patients, the new high-throughput approaches for cloning and
expression of IgG autoantibodies specific Gd-IgA1, high-resolution methods for structural analyses, and high-
throughput testing of inhibitors, our studies have progressed to a stage where molecular-level assessments of
the autoanti...

## Key facts

- **NIH application ID:** 9865737
- **Project number:** 1R01AI149431-01
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Todd Jason Green
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $515,750
- **Award type:** 1
- **Project period:** 2020-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9865737

## Citation

> US National Institutes of Health, RePORTER application 9865737, Pathogenic Autoantibodies with Specificity for Aberrant Glycoproteins: Assessment of a Therapeutic Target in an Autoimmune Disease (1R01AI149431-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9865737. Licensed CC0.

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