title: Association of rituximab with graphene oxide confers direct cytotoxicity for CD20-positive lymphoma cells.
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.
authors: Department of Spine Surgery, Xiangya Hospital of Central-South University, Changsha, China.
authors: Chengke
authors: C
authors: Luo
authors: Department of Pathology, University of Utah, Salt Lake City, Utah, USA.
authors: Zhenghao
authors: Z
authors: Deng
authors: Department of Pathology, University of Utah, Salt Lake City, Utah, USA.
authors: Lan
authors: L
authors: Li
authors: Department of Pathology, University of Utah, Salt Lake City, Utah, USA.
authors: Frederic
authors: F
authors: Clayton
authors: Department of Pathology, University of Utah, Salt Lake City, Utah, USA.
authors: Alexander L
authors: AL
authors: Chen
authors: Department of Pathology, University of Utah, Salt Lake City, Utah, USA.
authors: Ran
authors: R
authors: Wei
authors: Department of Pathology, University of Utah, Salt Lake City, Utah, USA.
authors: Rodney
authors: R
authors: Miles
authors: Huntsman Cancer Institute, Hematology Division, Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA.
authors: Deborah M
authors: DM
authors: Stephens
authors: Huntsman Cancer Institute, Hematology Division, Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA.
authors: Martha
authors: M
authors: Glenn
authors: Department of Spine Surgery, Xiangya Hospital of Central-South University, Changsha, China.
authors: Xiyang
authors: X
authors: Wang
authors: Department of Pathology, University of Utah, Salt Lake City, Utah, USA.
authors: Peter E
authors: PE
authors: Jensen
authors: Department of Pathology, University of Utah, Salt Lake City, Utah, USA.
authors: Xinjian
authors: X
authors: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects*; D006108:Graphite / Q000494:pharmacology; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D051379:Mice; D016688:Mice, Inbred NOD; D049329:Nanostructures / Q000737:chemistry*; D010087:Oxides / Q000494:pharmacology; D000069283:Rituximab / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010087:Oxides; D000069283:Rituximab; D006108:Graphite
keywords: CD20; Rituximab; graphene oxide; non-Hodgkin lymphoma