The article by Dr. McLaughlin and coauthors provides both a useful summary of the clinical trials involving rituximab(Drug information on 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.