Potent and broad neutralizing activity of a single chain antibody fragment against cell-free and cell-associated HIV-1.
نویسندگان
چکیده
Several human monoclonal antibodies (hmAbs) exhibit relatively potent and broad neutralizing activity against HIV-1, but there has not been much success in using them as potential therapeutics. We have previously hypothesized and demonstrated that small engineered antibodies can target highly conserved epitopes that are not accessible by full-size antibodies. However, their potency has not been comparatively evaluated with known HIV-1-neutralizing hmAbs against large panels of primary isolates. We report here the inhibitory activity of an engineered single chain antibody fragment (scFv), m9, against several panels of primary HIV-1 isolates from group M (clades A-G) using cell-free and cell-associated virus in cell line-based assays. M9 was much more potent than scFv 17b, and more potent than or comparable to the best-characterized broadly neutralizing hmAbs IgG(1) b12, 2G12, 2F5 and 4E10. It also inhibited cell-to-cell transmission of HIV-1 with higher potency than enfuvirtide (T-20, Fuzeon). M9 competed with a sulfated CCR5 N-terminal peptide for binding to gp120-CD4 complex, suggesting an overlapping epitope with the coreceptor binding site. M9 did not react with phosphatidylserine (PS) and cardiolipin (CL), nor did it react with a panel of autoantigens in an antinuclear autoantibody (ANA) assay. We further found that escape mutants resistant to m9 did not emerge in an immune selection assay. These results suggest that m9 is a novel anti-HIV-1 candidate with potential therapeutic or prophylactic properties, and its epitope is a new target for drug or vaccine development.
منابع مشابه
Production and Evaluation of Specific Single-Chain Antibodies against CTLA-4 for Cancer-Targeted Therapy
Background: Cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) molecules are expressed on T-cells and inhibit their function by inhibiting activation of subsequent T-cell molecular pathways. Blocking of CTLA-4 inhibits the growth of malignant tumor cells. Anti-CTLA-4 monoclonal antibodies activate the immune system against cancer. Due to several advantages of single-chain antibodi...
متن کاملSelection and Evaluation of Specific Single Chain Antibodies against CD90, a Marker for Mesenchymal and Cancer Stem Cells
Background: CD90, a membrane-associated glycoprotein is a marker used to identify mesenchymal stem cells (MSCs). Recent studies have introduced CD90, which induces tumorigenic activity, as a cancer stem cell (CSC) marker in various malignancies. Blocking CD90 activity with anti-CD90 monoclonal antibodies enhanced anti-tumor effects. To date, highly specific antibody single-chain variable fragme...
متن کاملDesign and Construction of a Novel Humanized Single-Chain Variable-Fragment Antibody against the Tumor Necrosis Factor alpha
The pro-inflammatory cytokine, TNF-α, which plays a major role in the development and persistence of inflammatory diseases, is the basis for the use of anti-TNF-α therapies. The neutralization of TNF-α or blockage of its binding to the corresponding receptor has mainly served as a therapeutic strategy against some diseases. This study aimed to investigate the production of a humanized single ch...
متن کاملDesign and Construction of a Novel Humanized Single-Chain Variable-Fragment Antibody against the Tumor Necrosis Factor alpha
The pro-inflammatory cytokine, TNF-α, which plays a major role in the development and persistence of inflammatory diseases, is the basis for the use of anti-TNF-α therapies. The neutralization of TNF-α or blockage of its binding to the corresponding receptor has mainly served as a therapeutic strategy against some diseases. This study aimed to investigate the production of a humanized single ch...
متن کاملConstruction of recombinant Pichia pastoris expressing single-chain antibody fragment against extracellular domain of EpCAM
Introduction: Epithelial cell adhesion molecule (EpCAM) is highly expressed on epithelial tumors. So, EpCAM is a valuable antigen for targeted therapy. Using monoclonal antibodies (mabs) is an attractive approach for targeted cancer therapy. Importantly, limitations of intact mabs including large size led to the development of antibody fragments such as single chain fragment variable (scfv). Pi...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- mAbs
دوره 2 3 شماره
صفحات -
تاریخ انتشار 2010