Inhibiting CD40 Ligand in Multiple Sclerosis: A Review of Emerging Therapeutic Potential

Abstract Purpose of Review Current high-efficacy disease-modifying therapies for multiple sclerosis (MS) primarily target adaptive immune cells in peripheral tissues, controlling focal inflammation (acute relapses and magnetic resonance imaging [MRI] activity). However, there is a need for new, safe therapies that address disease progression and disability accumulation in relapsing and progressive MS. The CD40/CD40L pathway, which regulates adaptive and innate immunity, is implicated in MS pathogenesis, making it a potential therapeutic target. Early clinical trials of anti-CD40L antibodies showed encouraging efficacy in autoimmune indications but were discontinued due to thromboembolic risk. Recent therapeutic advancements now allow researchers to leverage this pathway while reducing safety risks. Recent Findings Frexalimab is a humanized anti-CD40L immunoglobulin-G1 monoclonal antibody, Fc-engineered to overcome thromboembolic risk. It is the first second-generation anti-CD40L antibody being investigated in MS. In a randomized-controlled phase 2 trial, frexalimab was well-tolerated, showing rapid and sustained reduction in disease activity (assessed by MRI) while preserving lymphocyte levels. Summary Recent clinical findings strengthen the rationale for targeting CD40L in MS, supporting further development of anti-CD40L antibodies as potential high-efficacy, non-lymphocyte-depleting MS therapy. Further research is needed to understand the role of this pathway in MS pathogenesis and explore CD40L inhibition to address neuroinflammation and neurodegeneration, where unmet medical needs exist.