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

// Huafei Li 1, * , Ge Zhang 1, * , Cheng Jiang 1, * , Fulei Zhang 1, * , Changhong Ke 1, * , He Zhao 1 , Yun Sun 1 , Mengxin Zhao 1 , Di Chen 1 , Xiandi Zhu 1 , Li Zhang 1 , Bohua Li 1 , Jianxin Dai 1 , Wei Li 1, 2, 3 1 International Joint Cancer Institute, the Second Military Medical University, Shanghai, China 2 State Key Laboratory of Antibody Medicine and Targeting Therapy and Shanghai Key Laboratory of Cell Engineering, Shanghai, China 3 PLA General Hospital Cancer Center, PLA Graduate School of Medicine, Beijing, China * These authors have contributed equally to this work Correspondence to: Bohua Li, Wei Li, e-mail: liwei@smmu.edu.cn Keywords: nano mAb’s cluster, CD20, apoptosis, non-hodgkin lymphoma, rituximab Received: April 02, 2015 Accepted: May 18, 2015 Published: June 01, 2015 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.