The transmembrane receptor CD40 and its ligand (CD40L or CD154) are involved in initiating and sustaining the inflammatory response. While these responses are beneficial in infection and tumour lysis, chronic activation has been implicated in a range of neuroinflammatory and autoimmune conditions, including MS, Alzheimer’s disease and Parkinson’s disease.

With infection, CD40L on T cells is presented to CD40 on B cells, resulting in B cell activation and the production of proinflammatory cytokines (reviewed in Ots et al. Int J Mol Sci 2022;23:4115). An early observation was that targeting CD40L prevented the development of EAE, and substantially reduced severity after disease onset (Gerritse et al. Proc Natl Acad Sci U S A 1996;93:2499-2504). In MS, CD40L-expressing T cells infiltrate the CNS and activate CD40 receptors on microglia, resulting in the release of inflammatory cytokines, nitric oxide and matrix metalloproteinases that cause demyelination and increase blood-brain barrier permeability. Interferon-gamma enhances neuronal injury by CD40-activated microglia (Tan et al. J Neuroimmunol 1999;97:77-85).

A higher proportion of T cells express CD40L in MS subjects compared to healthy controls (Jensen et al. Eur J Neurol 2001;8:321-328). Higher levels of soluble CD40L in serum are able to distinguish SPMS from RRMS (Wu et al. J Cent Nerv Syst Dis 20212;13:11795735211050712). Interestingly, a tentative link has been described between Epstein-Barr viral (EBV) infection and CD40-CD40L. In a murine model of EBV infection, EAE more closely resembled MS (MS-like lesions, demyelination) if there was a latent viral infection (Casiraghi et al. Sci Rep 2015:5:13995), which may suggest that persistent infection may promote a chronic CD40L-mediated pro-inflammatory response.

Several approaches have been used to block CD40/CD40L-mediated microglial activation. An early proposal was peptide therapy (Kitagawa et al. Mod Rheumatol 2005;15:423-426), but this has not been actively pursued. The antibiotic minocycline downregulates CD40L expression on T cells (Giuliani et al. J Leukoc Biol 2005;78:135-143), which may explain the short-term benefits of minocycline in the Canadian Minocycline in MS Study (Metz et al. N Engl J Med 2017;376:2122-2133).

More recent studies have employed monoclonal antibodies to target CD40L. A phase I study reported that toralizumab increased the profile of anti-inflammatory cytokines (Fadul et al. Neurol Neuroimmunol Neuroinflamm 2021;8:e1096). However, further studies of this drug (and its sister compound ruplizumab) were stopped due to concerns about thromboembolic complications. It was theorized that CD40L-antibody complexes activated platelets and induced platelet aggregation (Detalle et al. Comp Med Chem 2017:622).

A novel compound, frexalimab (SAR441344), is now in development. Phase II results for the 12-week + 12-week extension were presented at ECTRIMS-ACTRIMS 2023. There was an 89% reduction in Gd+ lesions in the high-dose frexalimab group at 12 weeks; 96% had no Gd+ lesions and 91% had no new T2 lesions at week 24. The safety analysis will continue to a maximum of 148 weeks of drug exposure with full results expected next year.