Introduction
Neuromyelitis optica spectrum disorders (NMOSD) is an autoantibody-mediated, B cell-driven disorder of the central nervous system characterized by attacks of predominantly optic neuritis and longitudinally extensive transverse myelitis. An important feature of NMOSD is the presence of serum autoantibodies against aquaporin‑4, such as aquaporin-4-IgG, which is detected in about 80-90% of NMOSD patients (Jarius & Wildemann, 2010). Pathogenic aquaporin-4-IgG can be produced by a subpopulation of CD19-positive (CD19+) CD20‑negative (CD20-) B cells showing morphological and phenotypical properties of plasmablasts, which are selectively increased in peripheral blood in NMOSD patients (Chihara et al, 2011). Results of small, uncontrolled studies of the anti-CD20 monoclonal antibodies rituximab have provided some evidence for the therapeutic effect of B cell depletion in NMOSD (Cree et al, 2005; Jacob et al, 2008; Bedi et al, 2011; Kim et al, 2011; Ip et al, 2013). Compared to CD20, CD19 is expressed on a wider lineage of B cells, from pro-B to plasmablasts and some plasma cells. Direct depletion of CD19+ B cells could be more effective in reducing the risk of NMOSD attack by more effectively depleting plasmablasts producing aquaporin-4-IgG.
Inebilizumab is a humanized, affinity-optimized, afucosylated IgG1 kappa monoclonal antibody that binds to the B cell specific surface antigen CD19 resulting in the depletion of B cells, as well as plasmablasts and some plasma cells. Unlike the anti-CD20 monoclonal antibody rituximab, inebilizumab does not mediate complement dependent cytotoxicity (Herbst et al, 2010). The removal of fucose from the monoclonal antibody Fc results in approximately 10-fold increased affinity for the activating Fc gamma receptor IIIA and significantly enhances natural killer cell-mediated depletion of B cells via antibody-dependent cellular cytotoxicity and antibody‑dependent cellular phagocytosis mechanisms.
In a multicenter, double-blind, randomized, placebo-controlled Phase 2/3 study in adults with NMOSD (NCT02200770, N-MOmentum), inebilizumab treatment significantly reduced the onset of NMOSD attack (hazard ratio 0.272, p<0.0001 (Cree BAC et al, 2019). The objectives of this analysis were (1) to develop a population pharmacodynamic (PD) model describing the depletion of the peripheral B cell count by inebilizumab, and (2) to evaluate the relationship between inebilizumab pharmacokinetic (PK) exposure and efficacy endpoints in subjects with NMOSD.