Association of rituximab with graphene oxide confers direct cytotoxicity for CD20-positive lymphoma cells

Abstract

// Chengke Luo 1 , Zhenghao Deng 2 , Lan Li 2 , Frederic Clayton 2 , Alexander L. Chen 2 , Ran Wei 2 , Rodney Miles 2 , Deborah M. Stephens 3 , Martha Glenn 3 , Xiyang Wang 1 Peter E. Jensen 2 and Xinjian Chen 2 1 Department of Spine Surgery, Xiangya Hospital of Central-South University, Changsha, China 2 Department of Pathology, University of Utah, Salt Lake City, Utah, USA 3 Huntsman Cancer Institute, Hematology Division, Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA Correspondence to: Xinjian Chen, email: // Keywords : Rituximab, CD20, graphene oxide, non-Hodgkin lymphoma Received : December 08, 2015 Accepted : January 26, 2016 Published : February 07, 2016 Abstract Non-Hodgkin lymphoma (NHL) is one of the most common hematologic malignancies among adults for which the chimeric monoclonal anti-CD20 antibody (Ab) rituximab (RTX) is used as first-line therapy. As RTX itself is not directly cytotoxic but relies on host immune effector mechanisms or chemotherapeutic agents to attack target cells, its therapeutic capacity may become limited when host effector mechanisms are compromised. Currently, refractory disease and relapse with NHL are still common, highlighting the need for novel anti-CD20 antibody strategies with superior therapeutic efficacy over current protocols. We hypothesized that making RTX directly cytotoxic might improve the therapeutic efficacy. Graphene oxide (GO) has recently emerged as a highly attractive nanomaterial for biomedical applications; and several studies have reported cytotoxic effect of GO on benign and malignant cells in vitro . Herein, we report that RTX can be stably associated with GO, and that GO-associated RTX (RTX/GO) demonstrates remarkably high avidity for CD20. Binding of GO-associated RTX to CD20-positive lymphoma cells induces CD20 capping and target cell death through an actin dependent mechanism. In vivo, GO-associated RTX, but not free RTX, quickly eliminates high-grade lymphomas in the absence of host effector mechanisms in a xenograft lymphoma mouse model. Our findings represent the first demonstration of using GO-associated antibody as effective cytotoxic therapy for human B cell malignancies in the absence of chemotherapy, and these findings could have important clinical implications.