APRIL, a member of the tumor necrosis factor ligand superfamily, member 13 (TNFSF13, D256), is a proliferation-inducing ligand that binds to TNFRSF13B/TACI and TNFRSF17/BCMA, playing a role in regulating tumor cell growth. It may participate in monocyte/macrophage-mediated immune processes and play an important role in the treatment of IgA nephropathy.
APRIL expression distribution
APRIL is produced by several cell types, including myeloid cells (monocytes, macrophages, and dendritic cells), activated lymphocytes, and mucosal epithelial cells.
(Data source: Uniprot)
APRIL structure and its receptor
APRIL, encoded by the TNFSF13 gene on chromosome 17p13, is a secreted protein composed of 250 amino acids. Its biologically active state is as a trimer. APRIL exerts its effects through two cell surface receptors, TACI and BCMA. The binding sites of APRIL for these two receptors are located in specific regions of its trimer structure. In particular, the high-affinity receptor binding site (CRD2) is crucial for binding to TACI and BCMA.
TACI and BCMA receptors are primarily found on the surfaces of B lymphocytes and plasma cells; they can also be shed from the cell membrane and serve as decoy receptors for BAFF and APRIL. APRIL binds strongly to BCMA and with lower affinity to TACI . APRIL can bind to heparan sulfate proteoglycans within the extracellular matrix or on the surfaces of cells, including plasma cells, thereby increasing its local concentration and activity.
(Data source: Myette JR, et al. Kidney Int. 2019)
APRIL immunomodulatory effects
APRIL and BAFF form active soluble trimers and act on B cell receptors. APRIL can promote B cell maturation and plasma cell survival through BCMA. APRIL can also promote the class conversion of B cells to IgA and IgG producing cells through TACI.
(Data source: Cheung CK, et al. Kidney Int. 2024)
The role of APRIL in IgAN
The APRIL/BAFF axis is involved in the production of Gd-IgA1 ( galactose-deficient IgA1). In IgAN, circulating Gd-IgA1 increases, possibly due to extravasation from mucosal sites into the circulation or the mislocalization of B cells to systemic sites (such as the bone marrow) where Gd-IgA1 is produced. Increased circulating Gd-IgA1 is central to the pathogenesis of IgAN (IgA nephropathy).
(Data source: Cheung CK, et al. Kidney Int. 2024)
Targeted therapy for APRIL
in several autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis, alopecia areata, myasthenia gravis, bullous pemphigoid, Sjögren's syndrome, and multiple sclerosis, and are associated with worsening disease activity . APRIL and BAFF function as mediators of B cell survival and therapeutic targets in autoimmune diseases. Given the critical role of APRIL in IgAN , inhibitors targeting APRIL have emerged as potential therapeutic targets.
Sibeprenlimab (VIS649) is a humanized IgG2K monoclonal antibody that binds to human trimeric APRIL, blocking its interaction with TACI and BCMA. Sibeprenlimab has been shown to inhibit APRIL-induced B cell proliferation, including mature plasma cells , in vitro. In primate studies, sibeprenlimab treatment resulted in a dose-dependent reduction of serum IgA levels by up to 70%. Reductions in IgA+, IgM+, and IgG+ B cells were also observed in gastrointestinal tract-associated lymphoid tissues of treated animals. A Phase 2 study of VIS649 demonstrated a favorable safety profile, with no serious adverse events related to the study drug. A Phase 3 study evaluating the effect of sibeprenlimab 400 mg subcutaneously (sc) every four weeks on proteinuria and glomerular filtration rate is currently underway.
Atacicept, Telitacicept, and Povetacicept are drugs containing the extracellular domain of TACI that bind to BAFF and APRIL, thereby inhibiting their activity. These drugs are being studied in IgAN and other autoimmune diseases. A phase 2a study (Efficacy and Safety of Atacicept in the Treatment of IgA Nephropathy) involving 16 patients with IgAN demonstrated a dose-dependent reduction in proteinuria in patients treated with atacicept. A phase 2b trial demonstrated that atacicept is safe and well-tolerated. A phase 3 study of atacicept in lupus nephritis (LN) is currently in the planning stages (NCT05609812).
(Data source: Cheung CK, et al. Kidney Int. 2024)
