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Li H.,International Medical University | Zhang G.,International Medical University | Jiang C.,International Medical University | Zhang F.,International Medical University | And 12 more authors.
Oncotarget | Year: 2015

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 Rituximabresistant lymphomas in both disseminated and localized human NHL xenograft models. Further results revealed that ACNC is significantly potent in inducing caspasedependent 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. Source


Li W.,International Medical University | Li W.,State Key Laboratory of Antibody Medicine and Targeting Therapy | Wei H.,International Medical University | Li H.,International Medical University | And 5 more authors.
Nanomedicine | Year: 2014

Immunotherapy is a promising option for cancer treatment that might cure cancer with fewer side effects by primarily activating the host's immune system. However, the effect of traditional immunotherapy is modest, frequently due to tumor escape and resistance of multiple mechanisms. Pharmaceutical nanotechnology, which is also called cancer nanotechnology or nanomedicine, has provided a practical solution to solve the limitations of traditional immunotherapy. This article reviews the latest developments in immunotherapy and nanomedicine, and illustrates how nanocarriers (including micelles, liposomes, polymer-drug conjugates, solid lipid nanoparticles and biodegradable nanoparticles) could be used for the cellular transfer of immune effectors for active and passive nanoimmunotherapy. The fine engineering of nanocarriers based on the unique features of the tumor microenvironment and extra-/intra-cellular conditions of tumor cells can greatly tip the triangle immunobalance among host, tumor and nanoparticulates in favor of antitumor responses, which shows a promising prospect for nanoimmunotherapy. © 2014 Future Medicine Ltd. Source


Tong X.,International Medical University | Tong X.,Chinese PLA General Hospital | Tong X.,Shandong University | Li L.,Chinese University of Hong Kong | And 22 more authors.
Oncotarget | Year: 2014

SOX10 was identified as a methylated gene in our previous cancer methylome study. Here we further analyzed its epigenetic inactivation, biological functions and related cell signaling in digestive cancers (colorectal, gastric and esophageal cancers) in detail. SOX10 expression was decreased in multiple digestive cancer cell lines as well as primary tumors due to its promoter methylation. Pharmacologic or genetic demethylation reversed SOX10 silencing. Ectopic expression of SOX10 in SOX10-deficient cancer cells inhibits their proliferation, tumorigenicity, and metastatic potentials in vitro and in vivo. SOX10 also suppressed the epithelial to mesenchymal transition (EMT) and stemness properties of digestive tumor cells. Mechanistically, SOX10 competes with TCF4 to bind β-catenin and transrepresses its downstream target genes via its own DNA-binding property. SOX10 mutations that disrupt the SOX10-β-catenin interaction partially prevented tumor suppression. SOX10 is thus a commonly inactivated tumor suppressor that antagonizes Wnt/β-catenin signaling in cancer cells from different digestive tissues. Source


Shi X.,International Medical University | Deng Y.,Beijing Institute of Microbiology and Epidemiology | Deng Y.,State Key Laboratory of Pathogen and Biosecurity | Wang H.,International Medical University | And 19 more authors.
mAbs | Year: 2016

ABSTRACT: Although dengue virus (DENV) infection severely threatens the health of humans, no specific antiviral drugs are currently approved for clinical use against DENV infection. Attachment and fusion are 2 critical steps for the flavivirus infection, and the corresponding functional epitopes are located at E protein domain III (E-DIII) and domain II (E-DII), respectively. Here, we constructed a bispecific antibody (DVD-1A1D-2A10) based on the 2 well-characterized anti-DENV monoclonal antibodies 1A1D-2 (1A1D) and 2A10G6 (2A10). The 1A1D antibody binds E-DIII and can block the virus attaching to the cell surface, while the 2A10 antibody binds E-DII and is able to prevent the virus from fusing with the endosomal membrane. Our data showed that DVD-1A1D-2A10 retained the antigen-binding activity of both parental antibodies. Importantly, it was demonstrated to be significantly more effective at neutralizing DENV than its parental antibodies both in vitro and in vivo, even better than the combination of them. To eliminate the potential antibody-dependent enhancement (ADE) effect, this bispecific antibody was successfully engineered to prevent Fc-γ-R interaction. Overall, we generated a bispecific anti-DENV antibody targeting both attachment and fusion stages, and this bispecific antibody broadly neutralized all 4 serotypes of DENV without risk of ADE, suggesting that it has great potential as a novel antiviral strategy against DENV. © 2016 Taylor & Francis Group, LLC. Source


Zhu Y.,Anhui University of Science and Technology | Zhu Y.,Chinese Academy of Sciences | Dai J.,International Medical University | Dai J.,State Key Laboratory of Antibody Medicine and Targeting Therapy | And 20 more authors.
Journal of Biological Chemistry | Year: 2013

Background: The antibody 6C2 exhibited an unusually potent neutralizing ability against ricin. Results: We determined the crystal structure of 6C2 Fab in complex with RTA and mapped the epitope on RTA. Conclusion: The binding of 6C2 hinders the interaction between RTA and the ribosome, thus inhibiting the activities of RTA. Significance: Our findings further confirm the role of ribosomal elements in ricin activity and specificity. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc. Source

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