Company: VERA
Filing Date: 2025-02-28
Form Type: 10-K
Source: 0000950170-25-029969
Chunk: 179

Company: Vera Therapeutics, Inc.
Filing Date: 2025-02-28
Form: 10-K
Item: Item 1
Chunk 179
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 leading B-cell modulator therapy for IgAN. 

Pathophysiology of IgAN

The IgA antibody plays a key role in the immune system by protecting the body from foreign substances such as bacteria and viruses. Patients with IgAN produce elevated levels of Gd-IgA1. This abnormal glycosylation pattern of IgA1 is of central importance to the disease etiology.

As shown in Figure 1 below, a multi-step process leads to the ultimate development of progressive renal injury.

Figure 1: IgAN pathophysiology

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(1)B cells, which mature into plasma cells, are abnormally primed in the Peyer’s patch region of the ileum of the intestines, potentially due to a combination of genetic predisposition and environmental, bacterial or dietary factors. BAFF and APRIL are upregulated, leading to B cell maturation and survival, and antibody class switching, a mechanism that changes cells’ production from one immunoglobulin to another, causing an increase in the production of immunogenic Gd-IgA1.

(2)The Gd-IgA1 antibodies are immunogenic when found in the systemic circulation, and are recognized as an autoantigen by autoantibodies, or antibodies created by the body in response to a constituent of its own tissue. 

(3)Gd-IgA1 and anti-Gd-IgA1 autoantibodies combine to form pathogenic immune complexes, or clusters of antibodies.

(4)Pathogenic immune complexes are deposited and become trapped in the kidney’s glomeruli. This initiates an inflammatory response that damages the membranes. 

(5)As the glomeruli are destroyed, the kidney’s ability to remove waste products from the blood is reduced, and protein and blood leak into the urine. This can result in potentially life-threatening complications that lead to the need for dialysis or kidney transplant in many patients. 

Gd-IgA1 is central to the pathogenesis of IgAN

Gd-IgA1 is a subclass of IgA antibodies that lack units of galactose, a type of sugar, at the O-linked glycans of their hinge region. The hinge region is a stretch of amino acids in the IgA antibody. Circulating Gd-IgA1 antibodies have been shown to be the target of autoantigens for IgG antibodies with specificity for the hinge region.

A histopathological hallmark of IgAN is deposition of Gd-IgA1 in the gl