title: Construction and characterization of an anti-CD20 mAb nanocomb with exceptionally excellent lymphoma-suppressing activity.
abstract: The CD20-directed monoclonal antibody rituximab (RTX) established a new era in the treatment of non-Hodgkin lymphoma (NHL); however, suboptimal response and/or resistance to RTX still limit its clinical merits. Although four effector mechanisms are validated to participate in CD20-based immunotherapy, including complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, caspase-dependent apoptosis, and lysosome-mediated programmed cell death (PCD), they could hardly be synchronously activated by any anti-CD20 mAb or mAb derivative until now. Herein, a novel mAb nanocomb (polyethylenimine polymer-RTX-tositumomab [PPRT nanocomb]) was firstly constructed through mass arming two different anti-CD20 mAbs (RTX and tositumomab) to one polymer by nanotechnology. Comparing with free mAbs, PPRT nanocomb possesses a comparable binding ability and reduced "off-rate" to surface CD20 of NHL cells. When treated by PPRT nanocomb, the caspase-dependent apoptosis was remarkably enhanced except for concurrently eliciting complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and lysosome-mediated PCD. Besides, "cross-cell link"-assisted homotypic adhesion by PPRT nanocomb further enhanced the susceptibility to PCD of lymphoma cells. Pharmacokinetic assays revealed that PPRT nanocomb experienced a relatively reduced clearance from peripheral blood compared with free antibodies. With the cooperation of all the abovementioned superiorities, PPRT nanocomb exhibits exceptionally excellent in vivo antitumor activities in both disseminated and localized human NHL xenotransplant models.
authors.affiliation: International Joint Cancer Institute, Translation Medicine Institute, the Second Military Medical University, Shanghai, People's Republic of China ; Planning Division, Scientific Research Department, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, People's Republic of China ; Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Hua-Fei
authors.initials: HF
authors.lastname: Li
authors.affiliation: Department of Laboratory Diagnosis, Changhai Hospital, the Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Cong
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Cardiology, Changhai Hospital, the Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Ting
authors.initials: T
authors.lastname: Chen
authors.affiliation: International Joint Cancer Institute, Translation Medicine Institute, the Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.affiliation: International Joint Cancer Institute, Translation Medicine Institute, the Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: He
authors.initials: H
authors.lastname: Zhao
authors.affiliation: International Joint Cancer Institute, Translation Medicine Institute, the Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Chang-Hong
authors.initials: CH
authors.lastname: Ke
authors.affiliation: Planning Division, Scientific Research Department, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xu
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D018951:Antigens, CD20 / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D008223:Lymphoma; D050997:Nanomedicine / Q000379:methods*; D049329:Nanostructures / Q000737:chemistry*; D011094:Polyethyleneimine / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000069283:Rituximab / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D000069283:Rituximab; D011094:Polyethyleneimine
keywords: CD20; nanotechnology; non-Hodgkin lymphoma; programmed cell death; rituximab