Suppression of Rituximab-resistant B-cell lymphoma with a novel multi-component anti-CD20 mAb nanocluster.
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.
International Joint Cancer Institute, the Second Military Medical University, Shanghai, China.
Huafei
H
Li
International Joint Cancer Institute, the Second Military Medical University, Shanghai, China.
Ge
G
Zhang
International Joint Cancer Institute, the Second Military Medical University, Shanghai, China.
Cheng
C
Jiang
International Joint Cancer Institute, the Second Military Medical University, Shanghai, China.
Fulei
F
Zhang
International Joint Cancer Institute, the Second Military Medical University, Shanghai, China.
Changhong
C
Ke
International Joint Cancer Institute, the Second Military Medical University, Shanghai, China.
He
H
Zhao
International Joint Cancer Institute, the Second Military Medical University, Shanghai, China.
Yun
Y
Sun
International Joint Cancer Institute, the Second Military Medical University, Shanghai, China.
Mengxin
M
Zhao
International Joint Cancer Institute, the Second Military Medical University, Shanghai, China.
Di
D
Chen
International Joint Cancer Institute, the Second Military Medical University, Shanghai, China.
Xiandi
X
Zhu
International Joint Cancer Institute, the Second Military Medical University, Shanghai, China.
Li
L
Zhang
International Joint Cancer Institute, the Second Military Medical University, Shanghai, China.
Bohua
B
Li
International Joint Cancer Institute, the Second Military Medical University, Shanghai, China.
Jianxin
J
Dai
International Joint Cancer Institute, the Second Military Medical University, Shanghai, China.|State Key Laboratory of Antibody Medicine and Targeting Therapy and Shanghai Key Laboratory of Cell Engineering, Shanghai, China.|PLA General Hospital Cancer Center, PLA Graduate School of Medicine, Beijing, China.
Wei
W
Li
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D018951:Antigens, CD20 / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry*; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000276:immunology; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology; D008247:Lysosomes / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D018613:Microscopy, Confocal; D053758:Nanoparticles / Q000737:chemistry; D009368:Neoplasm Transplantation; D011094:Polyethyleneimine / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D000069283:Rituximab / Q000737:chemistry*
D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D011108:Polymers; D000069283:Rituximab; D011094:Polyethyleneimine; D020169:Caspases
CD20; Rituximab; apoptosis; nano mAb’s cluster; non-Hodgkin lymphoma