The article by Dr. McLaughlin and coauthors
provides both a useful summary of the clinical trials involving
rituximab (IDEC C2B8 [Rituxan]) and a practical guide for its
administration. Their review summarizes the most recent clinical
results with this monoclonal antibody, which have just been published
in the Journal of Clinical Oncology. The review also
includes a section on the potential mechanism of action of rituximab.
Several areas merit comment.
Rituximab is the first monoclonal antibody approved for the treatment
of malignancy and, as such, represents a major accomplishment for
IDEC Pharmaceuticals and the clinical investigators involved in the
antibodys development. It is appropriate to provide a short
historical perspective on monoclonal antibodies, as the successful
licensing of rituximab rests on the work of many individuals over
nearly 20 years.
The first trials of a monoclonal antibody involved T101, an anti-CD5
antibody pioneered by Dillman, Royston, and colleagues. These
trials were targeted against a variety of T-cell malignancies, as
well as chronic lymphocytic leukemia (CLL), which also expresses this
antigen, although at considerably lower levels. Rare, short-duration
responses were seen.
The next wave of excitement came from the work of Levy and Miller
with anti-idiotypic monoclonal antibodies; their first patient
achieved a long-term complete response to monoclonal antibody
therapy. Unfortunately, the response rate in the subsequent group
of patients was not as high. IDEC Pharmaceuticals was initially
founded to build on this experience.
Shortly after this work was published, several groups began exploring
CD20 as a target for immunotherapy, most notably, the group in
Seattle, who initially used 1F5. With the acquisition of
Schlossmans anti-B1 antibody by Coulter, anti-CD20 antibodies
were now radiolabeled and put into autologous transplantation
protocols by Press and colleagues. Even though this was a murine
immunoglobulin (IgG1), occasional responses were observed during the
dosimetry portion of the protocol when nontherapeutic doses of
isotope were administered. Evidently not missing these observations,
the investigators at IDEC switched emphasis from the anti-idiotypic
antibodies to a chimerized anti-CD20.
At about the same time, two other antilymphoma antibodies were also
in clinical trials, anti-TAC, developed by T. Waldmann et al, and
Campath-1H, developed by H. Waldmann et al. Both antibodies had
been humanized and were evaluated in a variety of clinical settings,
including lymphomas, as well as autoimmune processes.
Anti-TAC (anti-CD25) was not extremely active in treating lymphomas
and did not stand up to the scrutiny of phase III trials for the
treatment of graft-vs-host disease. This antibody is now being used
in radioimmunother-apy trials.
Campath-1H (anti-CD52) showed initial promise in the treatment of
lymphomas but has not achieved FDA licensing as yet. Recently,
Burroughs Wellcome licensed the development of this antibody to ILEX
and LeukoSite. These companies are currently conducting phase II
trials of the antibody in the treatment of CLL.
Why Was Rituximab the First MoAb to Win FDA Approval?
It is interesting to speculate as to why rituximab was the first
monoclonal antibody to be successful in achieving licensing. Several
factors seem to have contributed to this success: the antigen, the
human Fc portion of the monoclonal, the disease target, and the
clinical trial development.
CD20 is a fascinating antigen that is an integral membrane protein in
B cells (see Tedder and Engel for an excellent review). Anti-CD20
antibodies have been shown to trigger Ca2+ influx and thereby
cell-cycle events, leading either to entry into G1 or arrest in G1,
depending on the individual anti-CD20 antibody. Rituximab appears to
cause cell-cycle arrest.
Armed with a human gamma-1 Fc portion, anti-CD20 antibodies mediate
both complement-dependent cytotoxicity and antibody-dependent cell
mediated cytotoxicity. Although anti-CD20 antibodies can mediate
apoptosis in some malignant B-cell lines, this effect is small
compared to the growth arrest, unless a secondary antibody is added.
When rituximab is administered, pain and swelling of involved lymph
nodes are sometimes seen, suggesting an acute effect. Depletion of
com-plement levels has not been observed. The majority of responding
patients experience a slow regression of their tumors, indicating
that complement-mediated effects are not a major factor in eliciting
a response. The lack of modulation of CD20 and the ability of
rituximab to cause growth arrest with the possibility of mediating a
cellular response may provide insights into the success of this therapy.
In contrast, both CD5 and CD25 modulate, making the cellular
physiology much different than that of CD20. In addition, anti-CD5
antibodies are not known to cause growth arrest. Although anti-Tac
inhibits cell growth by blocking interleukin-2 (IL-2), it is not
clear whether it produces as strong a negative growth signal as does
rituximab. CD52 reportedly does not modulate; however, there are no
reports of the Campath-1H antibody mediating growth arrest.
A Special Target for Serotherapy
CD20, therefore, may represent a special target for serotherapy. It
not only may provide a stable target for mediating antibody-dependent
host effects but also may signal the cell to arrest, making it a more
stable target for the host. The cell-cycle arrest may also render the
cell more sensitive to certain chemotherapeutic reagents, making
combination therapy trials very attractive.
Although the authors mention ongoing trials with chemotherapy,
interestingly, they make no mention of other ongoing IDEC studies
with ytttrium-90 (IDEC Y2B8), despite the fact that the initial
trials look quite promising. It is possible that the cell
cyclealtering capabilities of this antibody could be exploited
to enhance this modality as well. The multiple capabilities of CD20
have recently been expanded to include its serving as an effective
target for anti-CD20 scFvFc-zetadirected T-cell killing.
With regard to the authors comments on the toxicity profile of
rituximab, the comparison to autologous bone marrow transplantation
programs is somewhat overstated. Clearly, the response rates and
minimal morbidity of rituximab are meritorious but do not warrant
comparison to treatments that are potentially curative in nature.
Andrew Raubitschek, MD is a participant in the IDEC RIT trials and
has colleagues who are participants in the C2B8 trials.
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chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent
lymphoma: Half of patients respond to a four-dose treatment program.
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2. Dillman RO, Shawler DL, Dillman JB, et al: Therapy of chronic
lymphocytic leukemia and cutaneous T-cell lymphoma with T101
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10. Wiseman G, Witzig T, White CA, et al: Radioimmunotherapy of
relapsed non-Hodgkins lymphoma (NHL) with IDEC-Y2B8 90-Yttrium
radioimmunotherapy. Abstract submitted to the American Society of
Clinical Oncology, May 1998.
11. Jensen M, Tan G, Forman S, et al: CD20 is a molecular target for
scFvFc:z receptor redirected T cells: Implications for cellular
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