Personalized Healthcare in Autoimmune Diseases - Genomic Biomarkers for Pharmaceutical Development - page 56

cell antigen CD20 is a 35-37 kD tetra-spanning integral membrane phosphoprotein that is highly
expressed by naïve, mature, and memory B cells, but not by precursor B cells and antibody-
producing plasma cells. This surface antigen is not shed by the cell and there are no detectable
levels of a soluble form in the serum [40] . Since this antigen is also expressed on the surface of
neoplastic B cells, it is an attractive target for B cell lymphoma and leukemia [40] . In addition to
these indications, RA, a chronic, disabling autoimmune disease characterized by synovial joint
arthritis and fatigue, has B cell involvement in its pathogenesis, associated with autoantibody
production leading to autoantibody / autoantigen complex deposits and tissue injury.
Rituximab, developed by Biogen Idec, a chimeric mouse / human IgG1mAb, is a CD20
antagonist that depletes CD20 naïve and memory B cells from the blood, bone marrow, and
lymph nodes by a mixture of apoptosis, antibody-dependent cell-mediated cellular cytotoxicity
(ADCC), and complement-dependent cytotoxicity (CDC) [41] . This molecule has demonstrated
efficacy in patients with RA who do not respond to anti-TNF mAb therapies, and has been
approved by the FDA for this patient population, in addition to patients with diffuse large B
cell lymphoma and chronic lymphocytic leukemia [42] . CD20+ B cell depletion (mean decrease
of 97%) in RA is essentially complete at one month after the start of a single treatment and sus-
tains for several months [43-46] . Peripheral B cells repopulate to almost baseline levels between
6 and 10 months after treatment [47,48] . Repopulation starts with the appearance of CD5+ /
CD38 high naïve B cells, followed by an increase in immature CD19- / IgD- / CD38 high / CD10 flow /
CD24 high B cells [46] ). Serum titers of rheumatoid factor (RF) and anti-citrullinated protein anti-
bodies (ACPA) significantly decreased at 24 and 36 weeks, respectively, whereas total immuno-
globulin levels and antibody titers against recall antigens were not affected. This finding may
suggest that rituximab selectively affects short-lived autoantibody-secreting plasma cells [47-
49] . The long-lasting depletion of peripheral blood B cells initially raised concerns with respect
to long-term safety. As it stands, the safety of rituximab is comparable to that of other biologic
Disease-modifying antirheumatic drugs (DMARDs). Adverse events were mild to moderate
infusion reactions observed in 2% of the rituximab-treated patients. Ocrelizumab is a human-
ized mAb that is the second generation antagonist for CD20 from Genentech and Biogen, and
this is currently being evaluated in multiple sclerosis in late stage clinical trials [42] .
Despite the effective depletion of circulating B cells in nearly all treated patients, a substan-
tial percentage of patients do not respond to rituximab treatment. In order to effectively utilize
rituximab and prevent unnecessary costs, risk of adverse effects, and delays in applying effec-
tive treatment, it is necessary to restrict treatment to only those patients who will benefit.
3.4.2 IgJ mRNA as a Predictive Marker of Non-response to Rituximab Therapy
in Patients with RA
A single transcript for IgJ has recently been developed as a biomarker to predict which RA
patients will show reduced clinical response to rituximab therapy [42] . In a post hoc analy-
sis, this biomarker was shown to be a consistent baseline predictor of poor response in RA
patients dosed with either rituximab or ocrelizumab, unlike those in patients administered
with placebo from four different clinical trials - DANCER, SERENE (NCT00299130), REFLEX
(NCT00468546), and SCRIPT (NCT00476996). RT-qPCR and flow cytometry assays were per-
formed on whole blood specimens from RA patients dosed with rituximab, ocrelizumab, or
placebo (depending on the clinical trial) at baseline and post dose time points. The specific