Tuesday, April 23, 2024 4/23/2024

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

Award Number: R01AI149431
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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 autoantibodies will advance our understanding of the mechanisms that drive IgAN disease. The results of our studies will define disease-specific targets to prevent pathogenic immune-complex formation in IgAN.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $464,175 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	5	2/15/2024	NON-COMPETING CONTINUATION	$464,175
														Subtotal = $464,175

Issue Date FY: 2023 ( Subtotal = $515,750 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	4	2/9/2023	NON-COMPETING CONTINUATION	$515,750
														Subtotal = $515,750

Issue Date FY: 2022 ( Subtotal = $515,750 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	3	3/1/2022	NON-COMPETING CONTINUATION	$515,750
														Subtotal = $515,750

Issue Date FY: 2021 ( Subtotal = $515,750 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	2	2/24/2021	NON-COMPETING CONTINUATION	$515,750
														Subtotal = $515,750

Issue Date FY: 2020 ( Subtotal = $515,750 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	1	3/1/2020	NEW	$515,750
														Subtotal = $515,750

Grand Total All Awards = $2,527,175

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

Award Number: R01AI149431

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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