MONITORING THE CELLULAR COMPONENTS OF THE IMMUNE SYSTEM DURING CLINICAL TRIALS: A TRANSLATIONAL MEDICINE APPROACH - Flow Cytometry in Drug Discovery and Development - page 193

replenishment. The B-cell repopulation was reported to be dominated by na ı ve B cells

(CD27 , IgD þ ). Moreover, the sustained low number of circulating memory B cells
(CD27 þ , IgD ) correlated with a reduction in serum rheumatoid factor and good
clinical outcomes. In contrast, an accumulation of memory B cells in the synovium
correlated with disease flare-ups [22].
Compounds in development targeting CD2 þ include Alefacept, a CD2 binding
chimeric protein. CD2 is expressed on all thymocytes, T cells, NK cells, and a small
subset of DC. The heterotypic interaction between CD2 and its major ligand CD58
(leukocyte function antigen (LFA)-3) enhances TCR-mediated signaling. CD2:CD58
interaction can also directly stimulate T-cell proliferation and differentiation inde-
pendent of TCR engagement. During clinical evaluation of Alefacept for psoriasis
vulgaris, flowcytometric assays were used to support primary efficacy objectives [29].
Analysis of total circulating T-cell levels as well as na ve, central memory, and

effector memory CD4 and CD8 T cells during treatment provided critical support to
the proof of concept for Alefacept. Selective decreases in circulating effector memory
T cells were observed after Alefacept treatment while the na

ı

ı ve T-cell population was

left intact.
Several monoclonal antibody-based cancer therapeutics are available on the
market (Ritxuan, Avastin, Herceptin, Erbitux, Vectibix, and Campath) with a greater
number in clinical development. Additional immunotherapeutics include cytokines,
adjuvants, and vaccines against oncogenic viruses. As such, the immune biomarkers
utilized for autoimmune conditions will also likely be applicable to oncology.

9.5 CLINICAL DRUG DEVELOPMENT II: RISK/BENEFIT
OF MONITORING CELLULAR COMPONENTS OF THE IMMUNE
SYSTEM DURING CLINICAL TRIALS

Quite a bit of information is available about lymphocyte subsets and the generation of
an immune response, including intracellular biochemical and molecular details, yet
much remains unknown particularly with regard to the whole animal model and the
clinical significance of specific immune subsets with respect to the pathophysiology
of immune-related disorders. Monitoring components of the immune system during
clinical testing has the potential to provide critical information on basic biology of the
immune system and insight into disease pathogenesis in addition to the primary
objective of gathering pharmacodynamic information. There are examples of bidir-
ectionality in translation medicine where information from drug development studies
feeds back to basic and clinical researchers. The success of B-cell depletion in
treatment of RA and SLE has increased the understanding of the role of B-cell
functions in rheumatic conditions. Furthermore, tracking B-cell replenishment has
provided valuable insight into the basic biology of B-cell ontogeny and trafficking.
Results of the clinical studies where selective depletion of memory T cells was
achievedwere valuable in underscoring the relative contribution of different cell types
to the pathogenesis of psoriasis. Moreover, much remains unresolved regarding the T-
cell differentiation pathway [9].