Synergistic anti-tumor therapy by a comb-like multifunctional antibody nanoarray with exceptionally potent activity.
Simultaneously blocking multiple mediators offers new hope for the treatment of complex diseases. However, the curative potential of current combination therapy by chronological administration of separate monoclonal antibodies (mAbs) or multi-specific mAbs is still moderate due to inconvenient manipulation, low cooperative effectors, poor pharmacokinetics and insufficient tumor accumulation. Here, we describe a facile strategy that arms distinct mAbs with cooperative effectors onto a long chain to form a multicomponent comb-like nano mAb. Unlike dissociative parental mAbs, the multifunctional mAb nanoarray (PL-RB) constructed from type I/II anti-CD20 mAbs shows good pharmacokinetics. This PL-RB simultaneously targets distinct epitopes on a single antigen (Ag) and neighboring Ags on different lymphocytes. This unique intra- and intercellular Ag cross-linking endows the multifunctional mAb nanoarray with potent apoptosis activity. The exceptional apoptosis, complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) that are synchronously evoked by the nano PL-RB are further synergistically promoted via enhanced permeability and retention (EPR), which resulted in high intratumor accumulation and excellent anti-lymphoma efficiency.
International Joint Cancer Institute, the Second Military Medical University, Shanghai 200433, China.
Huafei
H
Li
International Joint Cancer Institute, the Second Military Medical University, Shanghai 200433, China.
Yun
Y
Sun
International Joint Cancer Institute, the Second Military Medical University, Shanghai 200433, China.
Di
D
Chen
International Joint Cancer Institute, the Second Military Medical University, Shanghai 200433, China.
He
H
Zhao
International Joint Cancer Institute, the Second Military Medical University, Shanghai 200433, China.
Mengxin
M
Zhao
International Joint Cancer Institute, the Second Military Medical University, Shanghai 200433, China.
Xiandi
X
Zhu
International Joint Cancer Institute, the Second Military Medical University, Shanghai 200433, China.
Changhong
C
Ke
International Joint Cancer Institute, the Second Military Medical University, Shanghai 200433, China.
Ge
G
Zhang
International Joint Cancer Institute, the Second Military Medical University, Shanghai 200433, China.
Cheng
C
Jiang
International Joint Cancer Institute, the Second Military Medical University, Shanghai 200433, China.
Li
L
Zhang
International Joint Cancer Institute, the Second Military Medical University, Shanghai 200433, China.
Fulei
F
Zhang
International Joint Cancer Institute, the Second Military Medical University, Shanghai 200433, China.
Huafeng
H
Wei
International Joint Cancer Institute, the Second Military Medical University, Shanghai 200433, China.|State Key Laboratory of Antibody Medicine and Shanghai Key Laboratory of Cell Engineering, Shanghai 200433, China.|PLA General Hospital Cancer Center, PLA Graduate School of Medicine, Beijing 100853, China.
Wei
W
Li
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects / Q000276:immunology*; D018951:Antigens, CD20 / Q000276:immunology; D000970:Antineoplastic Agents / Q000276:immunology* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology*; D004357:Drug Synergism; D000939:Epitopes / Q000276:immunology / Q000494:pharmacology; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D008223:Lymphoma / Q000188:drug therapy / Q000276:immunology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D036103:Nanotechnology / Q000379:methods
D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D000939:Epitopes