CD40 is a critical costimulatory molecule belonging to the tumor necrosis factor receptor family, expressed by various cell types, including B cells, professional antigen-presenting cells (APCs), non-immune cells, and even tumors. The binding of CD40 to its ligand, CD40L (CD154), triggers the activation of dendritic cells (DCs), driving their maturation and equipping them with the necessary features to efficiently activate and differentiate T cells. This interaction is crucial for the survival of several cell types, including germinal center (GC) B cells, DCs, and endothelial cells, both under normal conditions and during inflammation. Given its pivotal role in immune regulation, CD40 signaling has garnered significant attention, with extensive research focusing on the therapeutic potential of CD40/CD40L modulation. This has led to the development of various CD40 targeting therapies, although none have been approved for clinical use as of December 2024; however, the first of these to enter the market by 2029 according Neeraj Chawla (Research Head) Kuick Research.
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The CD40/CD40L pathway plays a central role in the pathogenesis of numerous autoimmune diseases by contributing to immune system dysregulation. In autoimmune conditions like systemic lupus erythematosus (SLE), rheumatoid arthritis, and Sjögren’s syndrome, the excessive activation of this pathway exacerbates disease progression. This happens by promoting the activation of autoreactive B cells and the production of autoantibodies, along with disturbing T cell function, which can result in tissue damage. Because of its involvement in driving inflammation and autoimmunity, targeting the CD40/CD40L interaction is being explored as a potential therapeutic strategy. By modulating this pathway, researchers aim to reduce inflammation and limit the damage caused by these autoimmune processes.
On the other hand, in the context of cancer, CD40 targeting therapies are being developed to enhance the body’s immune response against tumors. Unlike traditional cancer treatments, such as chemotherapy and radiation, which indiscriminately damage both healthy and cancerous cells, CD40 targeted therapies aim to activate the immune system in a more specific and controlled manner. By stimulating the CD40 receptor, these therapies enhance dendritic cell function, promote antigen presentation, and trigger a robust anti-tumor immune response. This approach has the potential to improve cancer treatment by shifting the focus to boosting the body’s natural immune defenses rather than directly attacking tumor cells.
Several CD40/CD40L-targeting therapies have entered clinical trials for various diseases, with a few reaching phase 3 trials. One of the most notable candidates is Frexalimab (SAR441344), developed by Sanofi. Frexalimab is a second-generation monoclonal antibody that inhibits CD40L and is currently being investigated for the treatment of relapsing multiple sclerosis (MS). In phase 2 trials, Frexalimab demonstrated significant efficacy without depleting lymphocytes, suggesting it could be a breakthrough therapy for MS. As a result, Sanofi launched two phase 3 clinical trials, FREVIVA and FREXALT, in late 2023 to evaluate the therapy’s safety and effectiveness, both as a monotherapy and in combination with other treatments for different MS patient subsets.
The success of Frexalimab is only one of the many examples where CD40/CD40L-targeting therapies have been found to be effective, or even superior, to existing treatments. This growing body of evidence suggests that CD40-targeting therapies could play a key role in the future treatment of various immune-related diseases. While CD40 remains an underutilized therapeutic target, its complex role in immune regulation continues to draw considerable research attention. As clinical trials progress and researchers’ understanding of CD40/CD40L signaling deepens, these therapies are poised to become a critical component in the treatment of autoimmune diseases, cancer, and potentially other prevalent conditions, offering a more refined and effective way to modulate the immune system.