Suppression of Rituximab-resistant B-cell lymphoma with a novel multi-component anti-CD20 mAb nanocluster

Abstract

Although the anti-CD20 antibody Rituximab has revolutionized the treatment of Non-Hodgkin Lymphoma (NHL), resistance to treatment still existed. Thus, strategies for suppressing Rituximab-resistant NHLs are urgently needed. Here, an anti-CD20 nanocluster (ACNC) is successfully constructed from its type I and type II mAb (Rituximab and 11B8). These distinct anti-CD20 mAbs are mass grafted to a short chain polymer (polyethylenimine). Compared with parental Rituximab and 11B8, the ACNC had a reduced “off-rate”. Importantly, ACNC efficiently inhibited Rituximab-resistant lymphomas in both disseminated and localized human NHL xenograft models. Further results revealed that ACNC is significantly potent in inducing caspase-dependent apoptosis and lysosome-mediated programmed cell death (PCD). This may help explain why ACNC is effective in suppressing rituximab-resistant lymphoma while Rituximab and 11B8 are not. Additionally, ACNC experienced low clearance from peripheral blood and high intratumor accumulation. This improved pharmacokinetics is attributed to the antibody-antigen reaction (active targeting) and enhanced permeability and retention (ERP) effect (passive targeting). This study suggested that ACNC might be a promising therapeutic agent for treatment of rituximab-resistant lymphomas.

A developed antibody–drug conjugate rituximab-vcMMAE shows a potent cytotoxic activity against CD20-positive cell line

“…Nonetheless, rituximab, similar to most naked mAbs, displays limited clinical effectiveness mainly due to incidence of treatment resistance, relapse, as well as adverse side effects. Importantly, only 40% of the patients who initially respond to rituximab have the ability to respond again after relapse [6,7]. Therefore, there is a need for developing novel therapeutic strategies against rituximab-resistant B-cell lymphoma with improved outcomes.…”

Case 01-2017—Primary vitreoretinal lymphoma (PVRL): report of a case and update of literature from 1942 to 2016

“…Rituximab is a genetically engineered human monoclonal antibody directed against the B-lymphocyte specific antigen CD20 that is expressed only by hematopoietic and mature B cells (72,73). Rituximab was approved in 1997 to treat B-cell lymphoma and leukemia, and it has been shown to improve the outcome in PCNSL patients and reduce the CNS relapse rate in high-risk patients (74).…”

Induction of potent apoptosis by an anti-CD20 aptamer via the crosslink of membrane CD20 on non-Hodgkin's lymphoma cells

“…3A). 8,34 Briey, the PEI polymer (1 mg mL À1 ) was incubated with MPEGS linker under stirring and N 2 bubbling at room temperature for 4 h (PEI : MPEGS ¼ 1 : 15). Then, $SH modi-ed ACDA were slowly dropped into the MPEGS-PEI suspension and the reaction was conducted in an N 2 environment for 8 hours.…”

“…6,7 CD20 is a B-cell differentiating antigen, which selectively expressed on the surface of mature and malignant B-cells. 8 Currently, 5 anti-CD20 mAbs have been approved by the U.S. FDA (Food and Drug Administration): Rituximab (RTX, Rituxan), Ofatumumab (Arzerra), Obinutuzumab (Gazyva), the radio-conjugates Bexxar (Tositumomab-I 131 ) and Zevalin (Ibritumomab tiuxetan). 9,10 The rst FDA-approved RTX leads to target cell depletion mainly through complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC), which is used in all phases of conventional treatment, including rst-line therapy, maintenance and salvage therapy against CD20 + Non-Hodgkin's Lymphoma (NHL) in the clinic.…”