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Analyzing Tumor and Tissue Distribution of Target Antigen Specific Therapeutic Antibody
Published on: May 16, 2020
Construction and characterization of an anti-CD20 mAb nanocomb with exceptionally excellent lymphoma-suppressing
Hua-Fei Li1, Cong Wu2, Ting Chen3
1International 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.
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.
Insights
A novel rituximab (RTX) nanocomb, PPRT, enhances anti-cancer therapy by simultaneously activating multiple cell death pathways in non-Hodgkin lymphoma (NHL). This engineered antibody improves upon RTX efficacy against NHL.
Area of Science:
- Immunology
- Oncology
- Nanotechnology
Background:
- Rituximab (RTX) revolutionized non-Hodgkin lymphoma (NHL) treatment but faces challenges with suboptimal response and resistance.
- Current anti-CD20 monoclonal antibodies (mAbs) struggle to synchronously activate all four known effector mechanisms: complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), caspase-dependent apoptosis, and lysosome-mediated programmed cell death (PCD).
- This limits the full therapeutic potential of CD20-directed immunotherapy.
Purpose of the Study:
- To develop a novel anti-CD20 mAb construct capable of simultaneously activating multiple effector mechanisms for enhanced efficacy against NHL.
- To investigate the binding characteristics, cell death induction, and in vivo antitumor activity of the novel construct compared to free mAbs.
Main Methods:
- Construction of a novel mAb nanocomb (polyethylenimine polymer-RTX-tositumomab [PPRT nanocomb]) by conjugating two anti-CD20 mAbs (RTX and tositumomab) to a polymer backbone using nanotechnology.
- Assessment of binding affinity and off-rate to surface CD20 on NHL cells.
- Evaluation of effector functions (CDC, ADCC, apoptosis, lysosome-mediated PCD) and homotypic adhesion.
- Pharmacokinetic analysis and in vivo antitumor activity assessment in human NHL xenotransplant models.
Main Results:
- The PPRT nanocomb demonstrated comparable binding to CD20 with a reduced off-rate compared to free mAbs.
- PPRT nanocomb significantly enhanced caspase-dependent apoptosis and concurrently activated CDC, ADCC, and lysosome-mediated PCD.
- Enhanced homotypic adhesion via 'cross-cell link' further increased lymphoma cell susceptibility to PCD, and the nanocomb showed reduced peripheral blood clearance and potent in vivo antitumor activity.
Conclusions:
- The novel PPRT nanocomb effectively overcomes limitations of single-mechanism immunotherapies by synchronously activating multiple effector pathways.
- This multi-pronged attack strategy, combined with enhanced cell adhesion and favorable pharmacokinetics, results in superior in vivo antitumor efficacy against NHL.
- PPRT nanocomb represents a promising next-generation therapeutic for non-Hodgkin lymphoma.
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