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

Huafei Li; Ge Zhang; Cheng Jiang; Fulei Zhang; Changhong Ke; He Zhao; Yun Sun; Mengxin Zhao; Di Chen; Xiandi Zhu; Li Zhang; Bohua Li; Jianxin Dai; Wei Li

doi:10.18632/oncotarget.4206

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Research Papers:

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

Huafei Li _, Ge Zhang, Cheng Jiang, Fulei Zhang, Changhong Ke, He Zhao, Yun Sun, Mengxin Zhao, Di Chen, Xiandi Zhu, Li Zhang, Bohua Li, Jianxin Dai and Wei Li

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Oncotarget. 2015; 6:24192-24204. https://doi.org/10.18632/oncotarget.4206

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Abstract

Huafei Li1,*, Ge Zhang1,*, Cheng Jiang1,*, Fulei Zhang1,*, Changhong Ke1,*, He Zhao1, Yun Sun1, Mengxin Zhao1, Di Chen1, Xiandi Zhu1, Li Zhang1, Bohua Li1, Jianxin Dai1, Wei Li1,2,3

1International Joint Cancer Institute, the Second Military Medical University, Shanghai, China

2State Key Laboratory of Antibody Medicine and Targeting Therapy and Shanghai Key Laboratory of Cell Engineering, Shanghai, China

3PLA 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: [email protected]

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.

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Research Papers:

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

Abstract