BACKGROUND AND STUDY OBJECTIVES

Overactivation of the complement system can play a role in several inflammatory-mediated or complement-driven diseases. Selective targeting of the lectin pathway can potentially reduce complement activation in damaged tissues while still allowing complement to fight infections effectively. The study aimed to generate and evaluate a novel monoclonal antibody that targets MASP-2, the key effector enzyme of the lectin pathway. 

The Wieslab® Complement System Screen kit was used to assess the selectivity of inhibition by measuring pathway-specific complement activation. Activation of each pathway was detected with labeled antibodies, specific for neoepitopes of the terminal complement complex, C5b-9, produced during complement activation.

STUDY OUTCOMES

The researchers produced a fully human immunoglobulin gamma 4 (IgG4) monoclonal antibody to binds to MASP-2. They tested the selectivity of the antibody in human samples, and the results showed that the antibody inhibited lectin pathway-dependent activation and subsequent production of C5b-9 in human serum with high potency (IC50  ~1nM)  while not affecting classical or alternative pathway-dependent activation at concentrations up to 500 nM. 

Further pharmacological characterization confirmed the inhibition of the lectin pathway, which supports the investigation of narsoplimab in clinical settings. Currently, narsoplimab is being investigated in clinical trials of lectin pathway-mediated conditions, including hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA). 

The authors concluded that narsoplimab specifically binds to MASP-2 and functionally inhibits lectin-dependent complement activation without affecting the classical or alternative pathway.

CITATION

Dudler T, et al., Development and characterization of narsoplimab, a selective MASP-2 inhibitor, for the treatment of lectin-pathway-mediated disorders. Frontiers in Immunology. (2023) DOI: 10.3389/fimmu.2023.1297352