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Neddylation is required for herpes simplex virus type I （HSV- 1）-induced early phase interferon-beta production

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Cellular & Molecular Immunology 2016年第5期13卷 577-583页

作者： Xueying Zhang Zhenjie Ye Yujun Pei Guihua Qiu Qingyang Wang Yunlu Xu beifen shen Jiyan Zhang Department of Molecular Immunology Institute of Basic Medical Sciences 27 Taiping Road Beijing 100850 P. R. China Laboratory of Snake Venom Fujian Medical University 88 Jiaotong Road Fuzhou 350004 P. R. China

Type I interferons such as interferon-beta （IFN-β） play essential roles in the host innate immune response to herpes simplex virus type I （HSV-1） infection. The transcription of type I interferon genes is controlled by nuclear factor-κB （NF-κB） and interferon regulatory factor （IRF） family members including IRF3. NF-κB activation depends on the phosphorylation of inhibitor of κB （IκB）, which triggers its ubiqitination and degradation. It has been reported that neddylation inhibition by a pharmacological agent MLN4924 potently suppresses lipopolysaccharide （LPS）-induced proinflammatory cytokine production with the accumulation of phosphorylated IκBa. However, the role of neddylation in type I interferon expression remains unknown. Here, we report that neddylation inhibition with MLN4924 or upon UBA3 deficiency led to accumulation of phosphorylated IκBa, impaired IκBa degradation, and impaired NF-κB nuclear translocation in the early phase of HSV-1 infection even though phosphorylation and nuclear translocation of IRF3 were not affected. The blockade of NF-κB nuclear translocation by neddylation inhibition becomes less efficient at the later time points of HSV-1 infection. Consequently, HSV- 1-induced early phase IFN-β production significantly decreased upon MLN4924 treatment and UBA3 deficiency. NF-κB inhibitor JSH-23 mimicked the effects of neddylation inhibition in the early phase of HSV-1 infection. Moreover, the effects of neddylation inhibition on HSV-1-induced early phase IFN-c production diminished in the presence of NF-κB inhibitor JSH-23. Thus, neddylation contributes to HSV-l-induced early phase IFN-β production through, at least partially, promoting NF-κB activation.

关键词： innate immunity HSV-1 IFN-β NF-βB IRF3

cAMP Modulates Macrophage Development by Suppressing M-CSF-Induced MAPKs Activation

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Cellular & Molecular Immunology 2008年第2期5卷 153-157页

作者： Ning Zhu Jian Cui Chunxia Qiao Yan Li Yuanfang Ma Jiyan Zhang beifen shen Department of Molecular Immunology Institute of Basic Medical Sciences Beijing 100850 China Laboratory of Cellular and Molecular Immunology Henan University Kaifeng China These authors contributed equally to this work

M-CSF is a key cytokine in macrophage development by inducing MAPKs activation, and cAMP can inhibit MAPKs activation induced by inflammatory stimuli. To explore the effects of cAMP on M-CSF-induced MAPKs activation and on macrophage development, the model of bone marrow-derived murine macrophages （BMMs） was used. The effects of cAMP on M-CSF-induced MAPKs activation were analyzed by Western blotting assay, and the effects of cAMP on CD14 and F4/80 expression during macrophage development were examined by FACS analysis. Macrophage morphology showed the successful establishment of the model of macrophage development. Western blotting assay revealed that M-CSF activated ERK, JNK and p38 in both mature and immature macrophages, and cAMP inhibited M-CSF-induced ERK, JNK and p38 activation in a time-dependent manner. FACS analysis revealed that macrophage development was impaired with cAMP pretreatment. In conclusion, cAMP modulates macrophage development by suppressing M-CSF-induced MAPKs activation. Cellular ＆ Molecular Immunology.

关键词： macrophage development M-CSF cAME MAPKs

Active regions' setting of the extracellular ligand-binding domain of human interleukin-6 receptor

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Chinese Science Bulletin 2000年第13期45卷 1182-1187页

作者： Yunfang Ren Hong Qu Jiannan Feng Song Li beifen shen Institute of Basic Medical Sciences Academy of Military Medical Sciences Beijing China National Laboratory of Protein Engineering and Plant Genetic Engineering Peking University Beijing China Institute of Pharmacology and Toxicology Academy of Military Medical Sciences Beijing China

The reliable three dimensional (3-D) structure of the extracellular ligand-binding domain (V106-P322) of human interleukin-6 receptor (hlL-6R) has been constructed by means of computer-guided homology modeling techniques using the crystal structure of the extracellular ligand-binding region (K52-L251) of human growth hormone receptor (hGHR) as templet. The space location of some key residues which influence the combination ability between the receptor and the ligand has been observed and the effects of point mutagenesis of the four conservative cysteine residues on the space conformation are analyzed. The results show that the space conformation of the side-chain carboxyl of E305 plays a key role in the ligand-binding ability. Furthermore, the space conformation of the side-chain carboxyl of E305 is very important for the electrostatic potential complementarity between hlL-6R and hlL-6 according to the docking method.

关键词： human interleukin-6 receptor ligand-binding domain active region.

Human IgG1 C_γ1 Domain Is Crucial for the Bioactivity of the Engineered Anti-CD20 Antibodies

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Cellular & Molecular Immunology 2007年第2期4卷 121-125页

作者： Shusheng Geng Jiannan Feng Yan Li Xianjiang Kang Yingxun Sun Xin Gu Ying Huang Hong Chang beifen shen College of Life Science Hebei University Baoding China Institute of Basic Medical Sciences Beijing China Lab of Cellular and Molecular Immunology Medical School of Henan University Kaifeng China

In this study, we discussed the necessity of human IgG1 Cγ1 domain for recombinant antibody using computeraided homology modeling method and experimental studies. The heavy （VH） and light （VL） chain variable regions of 1-28, a murine IgM-type anti-CD20 mAb, were ligated by linker peptide （Gly4Ser）3 to form the single-chain Fv fragment （scFv）. Then, the engineered antibody （LH1-3） was generated by fusing scFv with the entire IgG1 heavy constant regions. The 3-D structure of LH1-3 was modeled using computer-aided homology modeling method and the binding activity of LH1-3 was evaluated theoretically. Compared to the 3-D structure of the Fv fragment of the parent antibody, the conformation of the active pocket of LH1-3 was remained because of the rigid support of Cγ1. Further experimental results of flow cytometry showed that the engineered anti-CD20 antibody possessed specifically binding activity to CD20-expressing target cells. The anti-CD20 antibody fragments could also mediate complement-dependent cytotoxicity （CDC） of human B-lymphoid cell lines. Our study highlights some interests and advantages of a methodology based on the homology modeling and analysis of molecular structural properties.

关键词： CD20 engineered antibody binding activity molecular modeling

Potent anti-angiogenesis and anti-tumor activity of a nove human anti-VEGF antibody, MIL60

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Cellular & Molecular Immunology 2014年第3期11卷 285-293页

作者： Jing Yang Qun Wang Chunxia Qiao Zhou Lin Xinying Li Yifei Huang Tingting Zhou Yan Li beifen shen Ming Lv Jiannan Feng Laboratory of Immunology Institute of Basic Medical Sciences Beijing China Department of Pathogens and Immunology Logistics College of Chinese People's Armed Police Forces Tianjin China Department of Ophthalmology General Hospital of People's Liberation Army Beijing China These authors contributed equally to this work

Angiogenesis is crucial for tumor development, growth and metastasis. Vascular endothelial growth factor （VEGF） has been implicated in promoting solid tumor growth and metastasis via stimulating tumor-associated angiogenesis, and blocking the activity of VEGF can starve tumors. Avastin, which is a humanized anti-VEGF antibody, has been successfully applied in clinics since 2004. However, the price of Avastin is extremely high for Chinese people. Here, we report a novel human anti-VEGF neutralizing antibody, MIL60, which shows an affinity comparable to that of Avastin （the KD value of MIL60 was 44.5 pM, while that of Avastin was 42.7 pM）. MIL60 displays favorable actions in inhibiting VEGF-triggered endothelial cell proliferation （the IC5o value of M IL60 was 31-6.4 ng/ml and that of Avastin was 47--.8.1 ng/ml）, migration （8 pg/ml or 0.8 pg/ml MIL60 versusthe control： P〈O.05） and tube formation （2 I^g/ml or 0.2 lzg/ml MIL60 versusthe control： P〈O.05） viathe VEGFR2 signaling pathway. Moreover, MIL60 was shown to inhibit tumor growth and angiogenesis in vivo in xenograft models of human colon carcinoma and ovarian cancer using immunotherapy and immunohistochemistry analysis （MIL60 versus N.S.： P=0.0007; Avastin versus N.S.： P=0.00046）. These data suggest that MIL60 is a potential therapeutic, anti-angiogenic agent. Our work provides a novel anti-VEGF antibody, which can be considered an anti-tumor antibody candidate and a new option for patients with various cancers.

关键词： angiogenesis anti-VEGF antibody cancer

Selection and characterization of the novel anti-human PD-1 FV78 antibody from a targeted epitope mammalian cell-displayed antibody library

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Cellular & Molecular Immunology 2018年第2期15卷 146-157页

作者： Longlong Luo Shi Wang Xiaoling Lang Tingting Zhou Jing Geng Xinying Li Chunxia Qiao Jiannan Feng beifen shen Ming Lv Yan Li Laboratory of Immunology Institute of Basic Medical SciencesBeijing100850China Laboratory of Cellular and Molecular Immunology Institute of ImmunologyHenan UniversityKaifeng475001China

Currently,display-based methods are well established and widely used in antibody engineering for affinity maturation and structural stability improvement.We obtained a novel anti-human programmed death 1(PD-1)antibody using computer-aided design and a mammalian cell display technology platform.We used computer-aided modeling and distance geometry methods to predict and assign the key residues that contributed to the binding of human PD-L1 to PD-1.Then,we analyzed the sequence of nivolumab(an anti-human PD-1 antibody,referred to as MIL75 in the article)to determine the template for antibody design and library construction.We identified a series of potential substitutions on the obtained template and constructed a virtual epitope-targeted antibody library based on the physicochemical properties and each possible location of the assigned key residues.The virtual antibody libraries were displayed on the surface of mammalian cells as the antigen-binding fragments of full-length immunoglobulin G.Then,we used flow cytometry and sequencing approaches to sort and screen the candidates.Finally,we obtained a novel anti-human PD-1 antibody named FV78.FV78 competitively recognized the PD-1 epitopes that interacted with MIL75 and possessed an affinity comparable to MIL75.Our results implied that FV78 possessed equivalent bioactivity in vitro and in vivo compared with MIL75,which highlighted the probability and prospect of FV78 becoming a new potential antibody therapy.

关键词： antibody computer-guided modeling distance geometry human PD-1 mammalian cell-displayed antibody library

High-Affinity Decoy PD-1 Mutant Screened from an Epitope-Specific Cell Library

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Engineering 2021年第11期7卷 1557-1565页

作者： Hao Liu Chunxia Qiao Naijing Hu Zhihong Wang Jing Wang Jiannan Feng beifen shen Yuanfang Ma Longlong Luo State Key Laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and ToxicologyBeijing 100850China Joint National Laboratory for Antibody Drug Engineering The First Affiliated HospitalSchool of MedicineHenan UniversityKaifeng 475004China School of Life Science and Biopharmaceutics Shenyang Pharmaceutical UniversityShenyang 110016China School of Basic Medicine and Clinical Pharmacy China Pharmaceutical UniversityNanjing 210009China

Immunotherapy with anti-programmed cell death protein-1(PD-1)/programmed cell death ligand-1(PDL1)monoclonal antibodies has become routine in the treatment of many kinds of human cancers,such as lung cancer,intestinal cancer,and melanoma.The PD-1/PD-L1 pathway inhibits T cell activation in the micro-environment,making it an attractive target against cancer.Wild-type(WT)PD-1 ectodomain has been shown to have difficulty blocking PD-1/PD-L1 mixture formation due to its low affinity.The present work uses three-dimensional(3D)crystal complex structures to analyze the interaction by which PD-1 binds to PD-L1 or PD-L2.It also reports on a theoretical study of the binding mode between PD-1 and its clinical antibody Opdivo.Based on the theoretical binding analysis of PD-1 and its ligands(i.e.,PD-L1 and PD-L2)or antibody(Opdivo),a small-content,epitope-oriented mammalian cell library was established for PD-1.After three rounds of cell sorting,the decoy PD-1 mutant 463,which presented a higher affinity than WT PD-1 to the PD-L1(the affinity has increased by almost three orders of magnitude)was screened out.It exhibited an inhibitory effect against PD-1 to prevent it from forming mixtures with PD-L1,which was similar to the effect of the commercial anti-PD-L1 antibody atezolizumab(ATE).The median effective concentration(EC50)value of the decoy mutant was 0.031 μg·mL^(-1) in comparison with 0.063 μg·mL^(-1) for ATE;both values were much lower than that of WT PD-1,at 2.571 μg·mL^(-1).The 463 decoy mutant reversed the inhibitory function of PD-1 in T cell activation;furthermore,10 mg·kg^(-1) of 463 inhibited about 75%of tumor growth in vivo in a MC38 transgenic xenograft mice model,which was similar to the activity of ATE.More interestingly,an even lower dose of 463(2 mg·kg^(-1))showed a better effect than 10 mg·kg^(-1) of WT PD-1.This work offers the decoy 463 with an improved curative effect,which holds potential to become a good option against PD-1/PD-L1-related cancers.

关键词： Decoy PD-1 PD-L1 Mammalian cell library Epitope-oriented

Characterization of a Novel Anti-DR5 Monoclonal Antibody WD1 with the Potential to Induce Tumor Cell Apoptosis

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Cellular & Molecular Immunology 2008年第1期5卷 55-60页

作者： Jing Wang Zhou Lin Chunxia Qiao Ming Lv Ming Yu He Xiao Qingyang Wang Liyan Wang Jiannan Feng beifen shen Yuanfang Ma Yan Li Laboratory of Cellular and Molecular Immunology Institute of Immunology Henan University Kaifeng China Institute of Basic Medical Sciences Beijing China These authors contributed equally to this work

TNF-related apoptosis-inducing ligand （TRAIL） is a TNF family member capable of inducing apoptosis. Death receptor 5 （DR 5） is a key receptor of TRAIL and plays an important role in TRAIL-induced apoptosis. To prepare monoclonal antibodies （mAbs） against DR5, cDNA encoding soluble DR5 （sDR5） was firstly amplified by reverse transcriptase-polymerase chain reaction （RT-PCR） with specific primers, and then inserted into a prokaryotic expression vector pET-30a. The recombinant plasmid was expressed in Escherichia coli strain BL21 （DE3）, and sDR5 was purified by nickel affinity chromatography. As an antigen, sDR5 was used to immunize mice. Hybridomas secreting antibodies against sDR5 were identified. One positive done was selected to produce antibody, WD1. ELISA and immunofluorescence demonstrated that WD1 could bind recombinant sDR5 and membranebound DR5 （mDR5） on Jurkat and Molt-4 cells. ATPLite assays showed that Jurkat and Molt-4 cells were sensitive to the antibody in a dose dependent manner. The Annexin V/PI assays and Giemsa＇s staining both showed that WD1 could induce Jurkat cell apoptosis efficiently. Transient transfection of 293T cells and indirect immunofluorescence assay demonstrated that mAb （WD1） couldn＇t cross-react with DR4. Our findings indicated that the novel antibody, WD1 could act as a direct agonist, bind DR5 characteristically, and initiate efficient apoptotic signaling and tumor regression. Thus, WD1 would be a leading candidate for potential cancer therapeutics. Cellular ＆ Molecular Immunology.

关键词： TRAIL death receptor 5 apoptosis monoclonal antibody ATPLite

A Novel Human Antibody,HF,against HER2/erb-B2 Obtained by a Computer-Aided Antibody Design Method

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Engineering 2021年第11期7卷 1566-1576页

作者： Chunxia Qiao Ming Lv Xinying Li Xiaoling Lang Shouqin Lv Mian Long Yan Li Shusheng Geng Zhou Lin beifen shen Jiannan Feng State Key Laboratory of Toxicology and Medical Countermeasures Institute of Pharmacology and ToxicologyBeijing 100850China Beijing Key Laboratory of Therapeutic Gene Engineering Antibody Beijing 100850China Institute of Military Cognitive and Brain Sciences Beijing 100850China Beijing Mabworks Biotech Co.Ltd. Beijing 100176China Institute of Mechanics Chinese Academy of SciencesBeijing 100190China

Fully human antibodies have minimal immunogenicity and safety profiles.At present,most potential antibody drugs in clinical trials are humanized or fully human.Human antibodies are mostly generated using the phage display method(in vitro)or by transgenic mice(in vivo);other methods include B lymphocyte immortalization,human–human hybridoma,and single-cell polymerase chain reaction.Here,we describe a structure-based computer-aided de novo design technology for human antibody generation.Based on the complex structure of human epidermal growth factor receptor 2(HER2)/Herceptin,we first designed six short peptides targeting the potential epitope of HER2 recognized by Herceptin.Next,these peptides were set as complementarity determining regions in a suitable immunoglobulin frame,giving birth to a novel anti-HER2 antibody named "HF,"which possessed higher affinity and more effective anti-tumor activity than Herceptin.Our work offers a useful tool for the quick design and selection of novel human antibodies for basic mechanical research as well as for imaging and clinical applications in immune-related diseases,such as cancer and infectious diseases.

关键词： HER2/erb-B2 Human antibody Computer-aided design