Since the approval of the first anti-CD20 monoclonal antibody, rituximab, in December 1997, significant advances have been made in moving this therapeutic modality forward to wide use in virtually all CD20-positive B-cell malignancies, as well as for many autoimmune diseases. While the clinical operation to advance rituximab has been quick, understanding how CD20 monoclonal antibodies mediate their direct effect and how we can improve them has been a slower process. Early work suggested that CD20 was neither internalized nor shed significantly, thereby justifying pursuit of this target for immune-based therapy.
CD20 antibodies mediate their biologic effects against tumor cells through antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity, and direct apoptosis. Type I CD20 antibodies (rituximab, ofatumumab) redistribute into lipid rafts, fix complement, mediate ADCC, and promote modest apoptosis only with cross linking. In contrast, type II CD20 antibodies (e.g., GA-101) remain outside of the rafts, lack significant complement fixation, mediate ADCC, and promote direct cell death through homotypic adhesion. Although type I CD20 antibodies are utilized in clinical practice, type II antibodies are still being tested in clinical trials with promising results. The finding that type II CD20 antibodies work well against CLL is quite exciting, as the type I antibodies have shown less (although still significant) efficacy.
A very promising series of studies by several different groups remind us that there is still much to understand about CD20 antibody-based treatment. In this latest paper, Mössner and colleagues from a biotechnology company in Switzerland demonstrated that type II CD20 antibodies are much more efficient than type I at depleting normal B cells in a human CD20 transgenic model that is dependent upon macrophages and Fcγ receptors. This difference in B-cell depletion relates to the degree of CD20 internalization following antibody binding. Specifically, type II antibodies undergo far less internalization and degradation than type I. Surprisingly, but in agreement with clinical data collected thus far, the authors demonstrated that internalization and degradation of type I CD20 antibodies is most pronounced in CLL, whereas it occurs less in other types of B-cell lymphoma. These data provide a rational explanation for why type II CD20 antibodies might be more effective in CLL and, again, are supportive of what has been observed to date in early phase I clinical trials of the first type II CD20 antibody, GA-101.
In Brief
The importance of this paper to B-cell immunotherapy is clear, and there are many lessons we can take from it. Despite the success of rituximab, and recently of atumumab, in several different B-cell malignancies and autoimmune diseases, our understanding of the mechanism by which this class of drug works is still very much evolving. The uniqueness of each neoplastic disease (CLL and NHL) and often contrasting mechanisms in pathologic, but not transformed, B cells must always be considered. For example, type II CD20 antibodies may be effective both for B-cell-dependent autoimmune diseases, where rituximab has had modest effect, and for CLL. In contrast, the benefit of type II CD20 antibodies in other types of lymphoma where antibody internalization and degradation are not as apparent may yield less significant improvements. Along with tailoring antibodies to specific diseases, we might also take better advantage of the antibody-cell interactions themselves. Type I antibodies are internalized with no measurable shaving, and this may make such antibodies ideal for the delivery of conjugated cytotoxic agents. Other possibilities undoubtedly exist and are waiting to be explored. As new therapeutic agents continue to be identified, early basic and translational investigation, such as that of Mössner et al. will form the foundation for tailoring and optimizing treatments, not only to each disease, but to each patient.
References
Competing Interests
Drs. Butchar and Byrd indicated no relevant conflicts of interest.
