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

Significance Statement

The novel fourth generation multifunctional nano based mAbs was developed by Prof. Wei Li’s group from International Joint Cancer Institute, the Second Military Medical University  

Since the first generation monoclonal antibodies (mAbs) like anti-CD20 (rituximab) was approved by Food and Drug Administration (FDA) in 1997, more than ten mAbs have been used for cancer therapy. For further boosting mAbs’ cellular cytotoxicity, the second generation mAb drug conjugates (ADC) was developed subsequently. It is known that simultaneous blocking multiple mediators by the third generation mAbs offers new hope for complex diseases treatment. But the curative potential of current combination therapy by chronological administration of separate mAbs or multi-specific mAbs is still moderate due to inconvenient manipulation, low cooperative effectors, poor pharmacokinetics and insufficient tumor accumulation. In addition, a lot of patients does not respond to mAbs and/or acquires resistance on long-term therapy.

Here, Dr. Wei Li from the International Joint Cancer Institute, the Second Military Medical University reports a facile strategy that armies distinct mAbs with cooperative effectors onto a long polymer chain to form a new multicomponent comb-like nano based mAb. Prof. Li said, “This should be the fourth generation of novel multifunctional mAbs”. In their experiments, the multifunctional nano based mAb, which was finely constructed from two distinct type I/II anti-CD20 mAbs (Rituximab and 11B8), shows good pharmacokinetics. The nano antibody can simultaneously binding with distinct epitopes on single CD20 antigen (Ag) and neighboring Ags on different lymphocytes. Such unique intra-/inter-cellular Ag’s crosslinking endows the nano mAb with potent apoptosis inducing ability. The potent effectors are further synergistically promoted via the enhanced permeability and retention (EPR) as shown in following Figure. Importantly, such nano based antibody formulation efficiently inhibited Rituximab-resistant lymphomas in both disseminated and localized human NHL xenograft models. Compared with its parental single molecular mAbs, this novel nano mAb’s modulates showed exceptionally potential for cancer therapy. Prof. Li said: “In the future, the cancer may be cured but not suppressed by such novel fourth generation multifunctional mAbs. We do hope the facile strategy could really revolutionize the treatment of many human malignancies.” They have applied related patents for intellectual property protection.

Figure legend

Scheme illustrates the finely design and fabrication of the multifunctional nano based mAbs and its corresponding potent synergetic therapeutic mechanism.

Suppression Rituximab-resistant B-cell lymphoma with novel multi-component anti-CD20 mAb nanocluster - global medical discovery

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Journal Reference

Oncotarget. 2015 Sep 15;6(27):24192-204.

Li H1, Zhang G1, Jiang C1, Zhang F1, Ke C1, Zhao H1, Sun Y1, Zhao M1, Chen D1, Zhu X1, Zhang L1, Li B1, Dai J1, Li W1,2,3.

Show Affiliations

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.

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.

Go To Oncotarget 

About The Author

 

Dr. Wei Li obtained his PhD from the Chinese University of Hong Kong in 2005 (supervised by Prof. Chi Wu), and then moved to Hong Kong Polytechnic University as a postdoctor in 2006 (with Prof. Pei Li). He worked in Tokyo Women’s Medical University as Assistant Professor since 2007 (with Prof. Teruo Okano). In 2010, he was recruited back to the Second Military Medical University (SMMU) as full professor by the special talent program, where he has established a state-of-the-art nanotherapy lab. The interdisciplinary research interest of his group is construction of intelligent nano-system and novel nano-antibody for advanced anticancer biotherapy. His work was renowned by nanoimmunotherapy and physical chemistry in nanomedicine. He is also adjunct professor PLA General Hospital (Beijing) and Liaocheng University (Shandong province).

Contact: 

Dr. Wei Li, Professor
International Joint Cancer Institute.
The Second Military Medical University800 Xiangying RoadShanghai 200433, China, E-mail: [email protected],
Phone: +86-21-81870804,  Fax: 86-21-81870801.

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