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Hybridomas, Genetic Engineering of 437

clonal antibodies as therapeutic agents. These humanized
antibodies do not elicit the HAMA effect and also the
half-life is much longer than mouse antibodies. Most
mouse IgG have a half-life of less than 20 h, whereas
an antibody with a human-type constant region can have a
half life of up to 21 days. Table III shows eight monoclonal
antibodies that have been approved by the U.S. regulatory
agency, the FDA for human therapeutic use. As well as
these, there are many more antibodies in clinical trials
with the expectation that the numbers in therapeutic use
will increase in the future.
The success of these chimeric antibodies can be il-
lustrated by Rituxan which is used in the treatment of
non-Hodgkin’s lymphoma. This has a murine variable re-
gion which binds specifically to CD20 on B cells and a
FIGURE 12 Use of antibodies in cancer therapy.
human Fc domain to trigger effector mechanisms. CD20
is a protein expressed by over 90% of the lymphoma cells.
cause the destruction of the target tumor cells (Fig. 12).
These tumor cells can become coated by the anti-CD20.
The conjugation of radioactive or toxic compounds to the
This results in activation of the complement pathway and
antibody can result in a localized high concentration re-
Fc receptor-bearing cells which can destroy the tumor
sulting in cytotoxicity. Alternatively, an enzyme may be
cell.
conjugated that will catalyze the release of a toxic product
from an ingested “pro-drug.” Another strategy is to pro-
mote an effector function through the use of a bispecific XVII. ANTIBODIES FROM PLANTS
antibody that could potentially activate T cells leading to
the specific destruction of the target cells. Antibodies were first expressed in transgenic plants in
The rationale behind these methods is to cause localized 1989. Since then various antibody fragments and domains
cell destruction but limit systemic toxicity. However, the have been produced in plant hosts as well as full-length
results of the initial clinical trials for therapeutic murine and multimeric antibodies. The most popular host species
antibodies using these strategies was disappointing. This for this work has been the tobacco plant, Nicotiana, al-
wasasaresultofunexpectedtoxicityassociatedwithtreat- though corn and soybeans have also been utilized. There
ment of immunoconjugates and the undesirable human is no apparent reason why other plants could not be used.
anti-mouse antibody (HAMA) immune response. How- The value of using plants for monoclonal antibody pro-
ever,theadministrationofantibodiesrelyingonaresponse duction include the absence of animal pathogens, the ease
within a short period of time period (up to 10 days) were of genetic manipulation, the ability of post-translational
more successful. This included antibodies for radioimag- modification, and the potential for scale-up to an economic
ing, radioimmunotherapy or for acute allograft rejection production process.
(the OKT3 antibody). Transformation involves the stable integration of the ap-
The development of human chimeric antibodies in the propriate DNA into the plant cell genome. The resulting
1990s increased rapidly the rate of licensing of mono- transgenic plants can be cross-fertilized so as to integrate

TABLE III Monoclonal Antibodies Approved by the FDA for Clinical Use
Antibody Type Therapeutic treatment Company Date approved
Orthoclone (OKT3) Murine Ig2a Allograft rejection Ortho Biotech 1986
ReoPro Chimeric (Fab) Coronary angioplasty Centocor/ Lilly 1994
Zenapax Humanized IgG1 Allograft rejection Protein Design/Hoffman-La Roche 1997
Rituxan Chimeric IgG1 Non-Hodgkin’s lymphoma Genentech 1997
Synagis Humanized IgG1 Respiratory synctial virus Medimmune 1998
Herceptin Humanized IgG1 Breast cancer Genentech 1998
Simulect Chimeric IgG1 Allograft rejection Novartis Pharm 1998
Inflixmab Chimeric IgG1 Rheumatoid arthritis/Crohn’s disease Centocor 1998–1999