Development of novel antibodies to autoreactive B cells as a potential therapeutic for SLE patients

. Systemic lupus erythematosus (SLE) is a chronic inflammatory disease that can affect multiple organs, with high morbidity and mortality. SLE is especially prominent in African Americans (AA) and yet AA still are the most understudied and underserved population among SLE patients. The pathogenic autoantibodies in SLE patients are produced by autoreactive B cells that escape normal tolerance mechanisms. The main difficulty in understanding how tolerance mechanisms are affected in SLE patients and how to treat these patients is the inability to identify and isolate autoreactive B cells. We analyzed the memory B cell repertoire in African American (AA) Sm+ SLE patients and healthy AA donors and found over-representation of B cells expressing one light (L) chain gene (V4-1) in all patients. We also found that 80% of these cells express autoreactive antibodies. Recently, we generated antibody (Ab) against this L chain and verified that it specifically recognizes B cells expressing the V4-1 L chain. In Aim 1, we will use this Ab in ELISA to determine the autoantigen specificity of V4-1-utilizing antibodies in serum of AA SLE patients, as well as the percent of total autoreactive Ab that express V4-1. We will use the anti-V4-1 Ab in combination with the previously identified 9G4 Ab (recognizing VH4-34 Ab, many of which are autoreactive) to determine the total percent of autoreactive antibodies and B cells that can be recognized and potentially depleted by these two Ab. These data will demonstrate if anti-V4-1 Ab, together with 9G4 Ab have therapeutic potential in SLE patients. In Aim 2, we will determine if the titer of V4-1-expressing Ab correlates with disease severity, and if the titers increase during active SLE episodes (flares). One of the most severe complications of SLE that disproportionally affects AA patients is lupus nephritis (LN). AA have a genetic predisposition to both SLE and chronic kidney disease, and AA patients with LN have higher rates of progression to end stage kidney disease. We will test if V4-1- and VH4-34-expressing B cells and Ab are present in kidneys of AA Sm+ SLE patients, which will indicate that these Ab are involved in the pathogenesis of LN. Further, we will identify H and L chain sequences and specificities of B cells other than V4-1+ and VH4-34+ B cells, that are present in patients' kidneys. Our long- term goal is to evaluate the potential of anti-V4-1 Ab to be used along with the previously identified 9G4 Ab, as a therapeutic to remove autoreactive B cells and Ab from AA lupus patients. Project Number: 1R21AI183127-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Olga Kalinina | Institution: LOYOLA UNIVERSITY CHICAGO, MAYWOOD, IL | Award Amount: $423,500 | Activity Code: R21 | Study Section: Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section[HAI] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21AI18312701A1