American Journal of Transplantation 2006; 6: 859–866
C ?2006 The Authors
Journal compilation C ?2006 The American Society of
Transplantation and the American Society of Transplant Surgeons
Rituximab, an Anti-CD20 Monoclonal Antibody:
History and Mechanism of Action
M. D. Pescovitz∗
Department of Surgery and Department of
Microbiology/Immunology Indiana Univ., Indianapolis, IN
∗Corresponding author: Mark D. Pescovitz,
Rituximab, chimeric anti-human CD20, is approved for
treatment of B-cell lymphoma in adults. It is being
used experimentally in other various immune-related
diseases such as immune thrombocytopenic purpura,
systemic lupus erythematosus, myasthenia gravis and
rheumatoid arthritis. In transplant recipients, it is used
for treatment of post-transplant lymphoproliferative
disease, to anecdotally reduce pre-formed anti-HLA
and anti-ABO antibodies and for the prevention and
treatment of acute rejection. This article primarily re-
views the science behind rituximab: its history, phar-
macokinetics and potential mechanism of action. A
need for controlled clinical trials is clearly indicated be-
fore the widespread use of this drug in transplant.
Key words: Anti-CD20, mechanism, pharmacokinet-
ics, rituximab, transplant
Received 23 October 2005, revised 1 December 2005
and accepted for publication 16 December 2005
While antibodies received early attention as a major mech-
anism of allograft injury (1,2), the major focus of recent im-
munosuppressive drug development has been on agents
that block the T-cell pathway. These anti-T-cell agents have
significantly reduced the rate of acute rejection and en-
hanced 1-year graft survival, but long-term graft survival,
as measured by graft half-life, has had only a marginal in-
crease. More recently, with attention to transplanting pa-
tients across ABO blood group differences or who have
circulating alloantibodies and coupled with increasing evi-
acute and chronic rejection, attention is again returning to
B cells with concerted efforts to develop protocols that
block their action. Cai and Terasaki recently annunciated
three categories of strategies to accomplish this goal: (1)
inhibition and depletion of antibody producing cells; (2) re-
moval or blockage of antibodies and (3) interference with
the mechanism of tissue injury (3). This review will de-
tail the state of the art of rituximab (Rituxan, Biogen-IDEC,
Genentech, San Francisco, CA) a drug being used in such
CD20 (human B-lymphocyte-restricted differentiation anti-
gen, Bp35), is a hydrophobic transmembrane protein with
a molecular weight of approximately 35 kD located on pre-
B and mature B lymphocytes (Figure 1) (4). The antigen is
expressed on most B-cell non-Hodgkin’s lymphomas but is
not found on stem cells, pro-B cells, normal plasma cells
or other normal tissues (Figure 2). Plasma blasts and stim-
ulated plasma cells may express CD20 (5). CD20 regulates
an early step(s) in the activation process for cell cycle ini-
tiation and differentiation, and possibly functions as a cal-
cium ion channel. CD20 is not shed from the cell surface
and does not internalize upon antibody binding (6). Free
CD20 antigen is not found in the circulation; thus a drug
that reacts with CD20, such as an antibody, would not be
neutralized before binding to its target cell (7).
Rituximab, a chimeric murine/human monoclonal antibody,
approved in the United States only for the treatment of
refractory or relapsed B-cell lymphomas, reacts with the
CD20 antigen (Figure 1) (8). It contains the complementar-
ity determining regions of the murine anti-CD20 antibody
constant region sequences. The vector was cloned into
Chinese hamster ovarian cells as the production source of
immunoglobulin (8). Rituximab is composed of two heavy
acids with a molecular weight of 145 kD. Rituximab has
a binding affinity for the CD20 antigen of approximately
8.0 nM, which is similar to the parent murine antibody,
The majority of pharmacokinetic and pharmacodynamic
studies have been performed in patients with B-cell lym-
phoma (7,9). In 9 patients given 375 mg/m2as an IV infu-
sion for four doses, the mean serum half-life was 59.8 h
(range 11.1 to 104.6 h) after the first infusion and 174 h
(range 26 to 442 h) after the fourth infusion. The serum
concentration of rituximab was directly correlated with re-
sponse and inversely correlated with tumor burden. The
wide range of half-lives may therefore reflect the variable
tumor burden among patients and the changes in CD20
positive (normal and malignant) B-cell populations upon re-
peated administrations. In a single-dose study in subjects
with renal failure, we found a substantially longer half-life
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American Journal of Transplantation 2006; 6: 859–866