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Immunology Program: A-623 in SLE and Autoimmune Diseases

Background and Pathophysiology
Systemic lupus erythematosus (SLE, also known as lupus) is an autoimmune disorder that involves multisystem microvascular inflammation which causes swelling, pain, and tissue damage throughout the body. SLE can affect any part of the body, but most often harms the heart, joints, skin, lungs, blood vessels, liver, kidneys and nervous system. The course of the diseases is unpredictable, with periods of illness (called flares) alternating with remission [38]. Although the specific cause of SLE is unknown, multiple factors are associated with the development of the disease. These include genetic, racial, hormonal, and environmental factors [39].

SLE is characterized by the production of autoantibodies to components of the cell nucleus; however, the precise knowledge of how these autoantibodies contribute to the disease is incomplete [40]. It is now accepted that B cells play a pivotal role in autoimmune diseases such as SLE. There is a growing body of published preclinical and clinical data that suggests that an overactivity of B cell responsiveness to immune stimulation may be an essential feature of SLE pathogenesis [41,42] and that this process could be independent of the production of autoantibodies [43].

Epidemiology
SLE primarily affects women, with a female to male ratio of about 9:1. Peak incidence occurs between ages 15 and 45, but ranges from infancy to advanced age. Some estimates put the worldwide SLE population at about 1.5 million with 500,000 in the US but a recent telephone survey commissioned by the Lupus Foundation of America suggested a prevalence of as many as 2,000,000 in the US [38].

Management
No therapeutics have been approved in the last 40 years for the treatment of SLE, presenting a large, unmet medical need. Today, most treatments for SLE only provide symptomatic relief. Current standard-of-care in SLE treatment include NSAIDs, corticosteroids, and immunosuppressants and carry potential risks of debilitating side effects [38]. Furthermore a proportion of patients do not respond to these conventional therapies.

The development of a therapeutic that is safer and/or more effective than current treatments would be a significant therapeutic advance.

A-623 Structure and Mechanism of Action: BAFF Inhibition
A-623 is an Fc-conjugated peptide that is being developed as a treatment for SLE based on its ability to bind to and antagonize the action of human cytokine called B cell activating factor of the TNF family (BAFF, also known in the literature as BLyS, TALL-1, THANK, and zTNF4). BAFF is a protein that is a critical survival factor for B cells and is required for B cell development and maintenance. BAFF acts by binding to 3 different receptors on B cells: BAFF-R, B-cell maturation (BCMA), and transmembrane activator and cyclophilin ligand interactor (TACI) [44]. Its involvement in B cell survival has been demonstrated in animal studies. Transgenic mice that overexpress BAFF exhibit symptoms similar to SLE. In addition, BAFF appears to be linked to autoimmune diseases such as SLE, Sjogren’s syndrome, and rheumatoid arthritis in which patients have elevated amounts of BAFF in serum samples [8,9,10,11,12,13]. Inhibition of BAFF is expected to block stages of B cell maturation, and subsequent antibody formation. Therefore, AMG 623 is a potential therapeutic agent for a broad range of B cell-mediated autoimmune and inflammatory diseases.