Monitoring of the Complement System Status in Patients With B-Cell Malignancies Treated With Rituximab

Frontiers in Immunology

Kinga Jaskuła¹  Aleksandra Jurkiewicz¹  Marcin Okrój¹  Grzegorz Stasiłojć¹  Anna Felberg¹  Aleksandra Urban¹  Michał Taszner²  Jan M. Zaucha²  Alan Majeranowski²  Anna M. Blom³ 

[1] Department of Cell Biology and Immunology, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, Gdańsk, Poland;Department of Hematology and Transplantology, Medical University of Gdańsk, Gdańsk, Poland;Department of Translational Medicine, Lund University, Malmö, Sweden;

关键词: obinutuzumab (GA101);    non-Hodgkin’s lymphoma;    complement system;    chronic lymphocytic leukemia;    rituximab;   

DOI  :  10.3389/fimmu.2020.584509

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown