Abstract
Rituximab is a pioneering anti-CD20 monoclonal antibody that became the first-line drug used in immunotherapy of B-cell malignancies over the last twenty years. Rituximab activates the complement system in vitro, but there is an ongoing debate on the exact role of this effector mechanism in therapeutic effect. Results of both in vitro and in vivo studies are model-dependent and preclude clear clinical conclusions. Additional confounding factors like complement inhibition by tumor cells, loss of target antigen and complement depletion due to excessively applied immunotherapeutics, intrapersonal variability in the concentration of main complement components and differences in tumor burden all suggest that a personalized approach is the best strategy for optimization of rituximab dosage and therapeutic schedule. Herein we critically review the existing knowledge in support of such concept and present original data on markers of complement activation, complement consumption, and rituximab accumulation in plasma of patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphomas (NHL). The increase of markers such as C4d and terminal complement complex (TCC) suggest the strongest complement activation after the first administration of rituximab, but not indicative of clinical outcome in patients receiving rituximab in combination with chemotherapy. Both ELISA and complement-dependent cytotoxicity (CDC) functional assay showed that a substantial number of patients accumulate rituximab to the extent that consecutive infusions do not improve the cytotoxic capacity of their sera. Our data suggest that individual assessment of CDC activity and rituximab concentration in plasma may support clinicians’ decisions on further drug infusions, or instead prescribing a therapy with anti-CD20 antibodies like obinutuzumab that more efficiently activate effector mechanisms other than complement.
Highlights
CD20, a surface molecule present on most developmental stages of B lymphocytes, fulfills many conditions attributable to being a promising target for immunotherapy [1,2,3,4,5]
The results obtained for chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphomas (NHL) patients are shown in Figures 1 and 2, respectively
One CLL patient (#18) showed spectacular, significantly lower complement-dependent cytotoxicity (CDC) of rituximab-supplemented post-infusion serum sample compared to the analogical pre-infusion sample and such CDC depletion was only observed at the first infusion (Figure 1 and Supplementary Statistics File)
Summary
CD20, a surface molecule present on most developmental stages of B lymphocytes, fulfills many conditions attributable to being a promising target for immunotherapy [1,2,3,4,5]. The first anti-CD20 immunotherapeutic rituximab was clinically approved in 1997 [6]. It became the first-line drug (usually in combination with chemotherapy), which significantly improved the survival of patients suffering from B cell leukemias and lymphomas [7, 8]. Our goal was to form coherent conclusions in the light of published data, with an emphasis on the role of the complement system. We supplement these conclusions with original data showing the status of the complement system and the retention of the drug in patients with B cell malignancies receiving rituximab. In our opinion, monitoring of such parameters contributes to a personalized therapeutic approach highly appreciated in patients undergoing treatment with anti-CD20 antibodies
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
