DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1016 have overcome the problems of variability in efficacy
and toxicity seen with the polyclonal products, but they
are more limited in their target specificity.
The first-generation murine monoclonal antibodies
have been replaced by newer humanized or fully
human monoclonal antibodies that lack antigenicity,
have a prolonged t 1/2
, and can be mutagenized to alter
their affinity to Fc receptors. Another class of biological
agents being developed for both auto-immunity and
transplantation are fusion receptor proteins. These
agents usually consist of the ligand-binding domains of
receptors bound to the Fc region of an immunoglobulin
(usually IgG 1
) to provide a longer t 1/2
. Examples of such
agents include abatacept (CTLA4-Ig) and belatacept (a
second-generation CTLA4-Ig), discussed later in “Costimulatory
Blockade.” Thus, polyclonal and monoclonal
antibodies as well as fusion receptor proteins
have a place in immunosuppressive therapy.
Antithymocyte Globulin
ATG is a purified gamma globulin from the serum of
rabbits immunized with human thymocytes (Regan
et al., 1999). It is provided as a sterile, freeze-dried
product for intravenous administration after reconstitution
with sterile water.
Mechanism of Action. ATG contains cytotoxic antibodies that bind
to CD2, CD3, CD4, CD8, CD11a, CD18, CD25, CD44, CD45, and
HLA class I and II molecules on the surface of human T lymphocytes
(Bourdage and Hamlin, 1995). The antibodies deplete circulating
lymphocytes by direct cytotoxicity (both complement and cell
mediated) and block lymphocyte function by binding to cell surface
molecules involved in the regulation of cell function.
Therapeutic Uses. ATG is used for induction immunosuppression,
although the only approved indication is
in the treatment of acute renal transplant rejection in
combination with other immunosuppressive agents
(Mariat et al., 1998). Antilymphocyte-depleting agents
(THYMOGLOBULIN, ATGAM, and OKT3) have been neither
rigorously tested in clinical trials nor registered for
use as induction immunosuppression. However, a metaanalysis
(Szczech et al., 1997) showed that antilymphocyte
induction improves graft survival. A course of
antithymocyte-globulin treatment often is given to renal
transplant patients with delayed graft function to avoid
early treatment with the nephrotoxic calcineurin
inhibitors and thereby aid in recovery from ischemic
reperfusion injury. The recommended dose for acute
rejection of renal grafts is 1.5 mg/kg/day (over 4-6
hours) for 7-14 days. Mean T-cell counts fall by day 2
of therapy. ATG also is used for acute rejection of other
types of organ transplants and for prophylaxis of rejection
(Wall, 1999).
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
Toxicity. Polyclonal antibodies are xenogeneic proteins that can elicit
major side effects, including fever and chills with the potential for
hypotension. Premedication with corticosteroids, acetaminophen,
and/or an antihistamine and administration of the antiserum by slow
infusion (over 4-6 hours) into a large-diameter vessel minimize such
reactions. Serum sickness and glomerulonephritis can occur; anaphylaxis
is a rare event. Hematologic complications include leukopenia
and thrombocytopenia. As with other immunosuppressive agents,
there is an increased risk of infection and malignancy, especially
when multiple immunosuppressive agents are combined. No drug
interactions have been described; anti-ATG antibodies develop,
although they do not limit repeated use.
Monoclonal Antibodies
Anti-CD3 Monoclonal Antibodies. Antibodies directed
at the ε chain of CD3, a trimeric molecule adjacent to
the T-cell receptor on the surface of human T lymphocytes,
have been used with considerable efficacy since
the early 1980s in human transplantation. The original
mouse IgG 2a
antihuman CD3 monoclonal antibody,
muromonab-CD3 (OKT3, ORTHOCLONE OKT3), still is
used to reverse glucocorticoid-resistant rejection
episodes (Cosimi et al., 1981).
Mechanism of Action. Muromonab-CD3 binds to the ε chain of CD3,
a monomorphic component of the T-cell receptor complex involved
in antigen recognition, cell signaling, and proliferation. Antibody
treatment induces rapid internalization of the T-cell receptor, thereby
preventing subsequent antigen recognition. Administration of the
antibody is followed rapidly by depletion and extravasation of a
majority of T cells from the bloodstream and peripheral lymphoid
organs such as lymph nodes and spleen. This absence of detectable
T cells from the usual lymphoid regions is secondary both to complement
activation-induced cell death and to margination of T cells
onto vascular endothelial walls and redistribution of T cells to nonlymphoid
organs such as the lungs. Muromonab-CD3 also reduces
function of the remaining T cells, as defined by lack of IL-2 production
and great reduction in the production of multiple cytokines, perhaps
with the exception of IL-4 and IL-10.
Therapeutic Uses. Muromonab-CD3 is indicated for
treatment of acute organ transplant rejection (Ortho
Multicenter Transplant Study Group, 1985).
Muromonab-CD3 is provided as a sterile solution containing
5 mg per ampule. The recommended dose is 5 mg/day (in adults; less
for children) in a single intravenous bolus (<1 minute) for
10-14 days. Antibody levels increase over the first 3 days and then
plateau. Circulating T cells disappear from the blood within minutes
of administration and return within ~1 week after termination of therapy.
Repeated use of muromonab-CD3 results in the immunization of
the patient against the mouse determinants of the antibody, which can
neutralize and prevent its immunosuppressive efficacy. Thus, repeated
treatment with the muromonab-CD3 or other mouse monoclonal antibodies
generally is contraindicated. The use of muromonab-CD3 for
induction and rejection therapy has diminished substantially in the
past 5 years because of its toxicity and the availability of ATG.