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.