Novel approach to MS therapeutics: anti-CD40L


CMSC 2023

An emerging therapeutic target of interest is CD40 and its ligand (CD40L), which initially drew attention for their role in activating B cells and macrophages in response to infection (reviewed in Ots et al. Int J Mol Sci 2022;23:4115). Subsequent investigations implicated abnormal CD40 expression in a number of neurological disorders, including multiple sclerosis.

For example, an increased proportion of dendritic cells have been shown to express CD40 in patients with RRMS and SPMS compared to healthy controls; CD40 expression was associated with higher levels of Th1 proinflammatory cytokines such as interferon-gamma and TNF-alpha (Karni et al. J Immunol 2006;177:4196-202). CD40 ligation produces soluble forms of CD40 and CD40L; sCD40L is associated with disruption of the blood-brain barrier (Masuda et al. J Neuroimmunol 2017;305:102-107) and with disease progression in MS (Wu et al. J Cent Nerv Syst Dis 2021;13:11795735211050712).

T cells expressing CD40L have been shown to infiltrate the CNS and activate CD40 receptors on microglia, which induces the release of inflammatory factors (cytokines, nitric oxide) that contribute to demyelination (Aarts et al. Front Immunol 2017;8:1791). CD40/CD40L interactions may also promote inflammatory damage in the CNS compartment by CD8+ T cells and antibodies (Otts 2022).

These and other findings led to a first generation of monoclonal antibody therapies directed at CD40/CD40L. However, the development of these MAbs (e.g. ruplizumab [BG9588]) was halted due to thromboembolic complications in clinical trials (Kawai et al. Nat Med 2000;6:114). This adverse effect was ultimately attributed to the Fc component of the MAbs, which formed anti-CD40L immune complexes that led to platelet aggregation and thrombosis.

Second-generation MAbs were thus engineered without the Fc portion. Phase II data for the first of these second-generation agents, frexalimab (SAR441344), were presented at the Consortium of MS Clinics (CMSC) annual meeting (Vermersch et al. CMSC 2023;LB03).

The phase II trial randomized 129 RMS subjects to higher- or lower-dose frexalimab (doses not specified) or placebo for 12 weeks followed by a 12-week open-label of extension. The primary outcome was the number of Gd+ lesions at week 12 vs. week 8. Mean age at entry was 36.6 years; mean duration from MS symptom onset was 7.7 years; median EDSS score was 2.5; and 30% had Gd+ lesions at baseline. There was a significant reduction in Gd+ lesions in the higher- and lower-dose frexalimab groups versus placebo (0.2 and 0.3 lesions/scan vs. 1.4, a 79-89% reduction). In the higher-dose group, the proportion free of Gd+ lesions was 85% at week 12 and 96% at week 24. The change from baseline in plasma neurofilament-light (NfL) levels was -26% and -20% in the higher- and lower-dose dose groups, respectively, versus placebo at week 12.  No serious adverse events were reported. The most common adverse effects were COVID-19 infection (mild to moderate) and headache. There was one case of elevated liver enzymes.

Other potential applications of anti-CD40L MAbs include autoimmune and neuroinflammatory conditions such as myasthenia gravis and amyotrophic lateral sclerosis. Also of interest is Alzheimer’s disease since CD40 has been implicated in formation of beta-amyloid plaques and neurofibrillary tangles.

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