Narsoplimab

Transplant-associated thrombotic microangiopathy (TA-TMA) has complex underlying pathophysiology but generally involves complement activation associated with endothelial injury, microthrombus development, and downstream organ dysfunction. Studies have demonstrated a role for the alternative and lectin complement pathways in TMA. Within the lectin pathway, considerable interest has fallen on the effector protein mannan-associated lectin-binding serine protease-2 (MASP-2), which cleaves C4 and C2 to form the C3 convertase C4bC2a.

Narsoplimab is a human IgG4λ monoclonal antibody targeted against MASP-2. By inhibiting MASP-2, it blocks lectin-dependent activation of complement components C3 and C4, without affecting the classical or alternative complement pathways. In the context of hematopoietic stem cell TA-TMA, this inhibition is thought to prevent lectin pathway-mediated cellular injury, specifically endothelial cell injury in small blood vessels. This mechanism is distinct from C5 inhibition (e.g., eculizumab), as it targets the pathway at its initial steps rather than the terminal phase, potentially avoiding widespread damage while leaving other innate immunity pathways intact.