Ronald P. Taylor, PhD
Role of complement in the action of anti-tumor monoclonal antibodies
The Taylor laboratory is focused on developing technologies, which make use of the complement system and cellular based mechanisms in targeted killing of cancer cells. For example, the lab developed and patented mAbs, specific for complement fragment C3b, which enhance killing of cancer cells when they are opsonized with complement. Their work is based on a bench to bedside and back to the bench paradigm; they are making basic science measurements, which allow them to initiate collaborations with clinical investigators, and the results of the clinical studies lead them to address new questions in the laboratory. The approach is illustrated in their recent findings in studying the mechanism of action of Rituximab (RTX, anti-CD20) when it is used to treat patients with Chronic Lymphocytic Leukemia. They recently reported that during the usual therapeutic infusion of RTX in patients with chronic lymphocytic leukemia (CLL), a large fraction of malignant cells were rapidly cleared from the circulation early in the infusion, after ~ 30 mg of RTX were infused. As the infusion continued, the number of malignant cells in the circulation increased, and by the end of the infusion (700 mg RTX infused), the concentration of RTX in the bloodstream was quite high (>100 ug/ml), and substantial B cell recrudesence was evident. Importantly, most of the recrudesced B cells had very low levels of CD20, and the lab found that the target CD20 had been removed from the cells, a phenomenon previously called "antigenic modulation." They reasoned that the dose of RTX was too high, and they initiated and completed a Phase I Pilot study in collaboration with Dr Williams and his colleagues in Hematology/Oncology, and they determined that much lower doses of RTX, given thrice weekly, appeared to be far more effective and prevented antigenic modulation. Additional, more extensive clinical trials are planned.
The lab is now investigating the loss of CD20 from B cells in both a pre-clinical mouse model and in an vitro model system. Binding of RTX to several CD20+ cell lines as well as to B cells from CLL patients leads to rapid and substantial antigenic modulation when the RTX-opsonized cells are incubated with acceptor THP-1 cells, a monocytic cell line. Their experiments reveal that the RTX-CD20 complexes are removed from the opsonized cells and are taken up by the THP-1 cells, in a process they have identified as the "shaving reaction". This shaving reaction, which clearly occurs in vivo, can compromise the efficacy of RTX-based therapy of CLL, and may explain why RTX as a single agent has indeed had limited success in CLL treatment. They hope to develop treatment paradigms that preserve cell killing, but abrogate or minimize shaving/antigenic modulation; the low dose RTX therapy is a first step. The lab is investigating the general implications of our findings. In particular, preliminary in vitro data indicates that several other therapeutic mAbs induce antigenic modulation, and if these observations can be confirmed both in the lab and in future clinical studies, their findings may have major implications for other mAb/target systems in use or under investigation for the immunotherapy of cancer.