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| 1 | Binding Activity Difference of Anti-CD20 scFv-Fc Fusion Protein Derived from Variable Domain Exchange显示文摘Two novel engineered antibody fragments binding to antigen CD20 were generated by fusing a murine IgM-type anti-CD20 single-chain Fv fragment (scFv) to the human IgG1 CH2 (i.e., Cγ2) and CH3 (i.e., Cγ3) domains with the human IgG1 hinge (i.e. Hγ). Given the relationship between structure and function of protein, the 3-D structures of the two engineered antibody fragments were modeled using computer-aided homology modeling method. Furthermore, the relationship between 3-D conformation and their binding activity was evaluated theoretically. Due to the change of active pocket formed by CDRs, the HL23 (VH-Linker-VL-Hγ-Cγ2-Cγ3) remained its activity because of its preserved conformation, while the binding activity of the LH23 (VL-Linker-VH-Hγ-Cγ2-Cγ3) was impaired severely. Experimental studies by flow cytometry and fluorescence microscopy showed that HL23 possessed significantly superior binding activity to CD20-expressing target cells than LH23. That is to say, the order of variable regions could influence the binding activity of the fusion protein to CD20+ cell lines, which was in accordance with the theoretical results. The study highlights the potential relationship between the antibody binding activity and their 3-D conformation, which appears to be worthwhile in providing direction for future antibody design of recombinant antibody. | Shusheng Geng Jiannan Feng Yan Li Yingxun Sun Xin Gu Ying Huang Yugang Wang Xianjiang Kang Hong Chang Beifen Shen | 2006 | Cellular & Molecular Immunology2006，3，6： | 13 |
| 2 | Characterization of the neutralizing activity of three anti-human TNF monoclonal antibodies and prediction of their TNF epitopes by molecular modeling and mutant protein approach显示文摘 | Cansheng Zhu Xuesong Liu Jiannan Feng Wei Zhang Beifen Shen Weiming Ou'yang Yunxin Cao Boquan Jin | 2006 | 中国生物学文摘2006，20，1： | 5 |
| 3 | Neddylation is required for herpes simplex virus type I (HSV- 1)-induced early phase interferon-beta production显示文摘 | Xueying Zhang Zhenjie Ye Yujun Pei Guihua Qiu Qingyang Wang Yunlu Xu Beifen Shen Jiyan Zhang | 2016 | Cellular & Molecular Immunology2016，13，5： | 5 |
| 4 | Potent anti-angiogenesis and anti-tumor activity of a nove human anti-VEGF antibody, MIL60显示文摘 | Jing Yang Qun Wang Chunxia Qiao Zhou Lin Xinying Li Yifei Huang Tingting Zhou Yan Li Beifen Shen Ming Lv Jiannan Feng | 2014 | Cellular & Molecular Immunology2014，11，3： | 4 |
| 5 | Selection and characterization of the novel anti-human PD-1 FV78 antibody from a targeted epitope mammalian cell-displayed antibody library显示文摘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. | Longlong Luo Shi Wang Xiaoling Lang Tingting Zhou Jing Geng Xinying Li Chunxia Qiao Jiannan Feng Beifen Shen Ming Lv Yan Li | 2018 | Cellular & Molecular Immunology2018，15，2： | 4 |
| 6 | cAMP Modulates Macrophage Development by Suppressing M-CSF-Induced MAPKs Activation显示文摘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. | Ning Zhu Jian Cui Chunxia Qiao Yan Li Yuanfang Ma Jiyan Zhang Beifen Shen | 2008 | Cellular & Molecular Immunology2008，5，2： | 4 |
| 7 | Characterization of a Novel Anti-DR5 Monoclonal Antibody WD1 with the Potential to Induce Tumor Cell Apoptosis显示文摘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 clone was selected to produce antibody,WD1. ELISA and immunofluorescence demonstrated that WD1 could bind recombinant sDR5 and membrane-bound 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. | Jing Wang Zhou Lin Chunxia Qiao Ming Lv Ming Yu He Xiao Qingyang Wang Liyan Wang Jiannan Feng Beifen Shen Yuanfang Ma Yan Li | 2008 | Cellular & Molecular Immunology2008，5，1： | 4 |
| 8 | The Effect of CD3-Specific Monoclonal Antibody on Treating Experimental Autoimmune Myasthenia Gravis显示文摘CD3-specific monoclonal antibody was the first one used for clinical practice in field of transplantation. Recently,renewed interests have elicited in its capacity to prevent autoimmune diabetes by inducing immune tolerance. In this study, we tested whether this antibody can also be used to treat another kind of autoimmune disease myasthenia gravis (MG) and explored the possible mechanisms. MG is caused by an autoimmune damage mediated by antibody- and complement-mediated destruction of AChR at the neuromuscular junction. We found that administration of CD3-specific antibody (Fab)2 to an animal model with experimental autoimmune myasthenia gravis (EAMG) (B6 mice received 3 times of AChR/CFA immunization) could not significantly improve the clinical signs and clinical score. When the possible mechanisms were tested, we found that CD3 antibody treatment slightly down-regulated the T-cell response to AChR, modestly up-regulation the muscle strength. And no significant difference in the titers of IgG2b was found between CD3 antibody treated and control groups. These data indicated that CD3-specific antibody was not suitable for treating MG, an antibody- and complementmediated autoimmune disease, after this disease has been established. The role of CD3-specific antibody in treating this kind of disease remains to be determined. | Ruonan Xu~1 Jianan Wang~1 Guojiang Chen~1 Gencheng Han~1 Renxi Wang~1 Beifen Shen~1 Yan Li~(1,2) ~1Institute of Basic Medical Science,Academy of military Medical Science,Beijing 100850,China ~2Department of Molecular Immunology,Institute of Basic Medical Science,27 Taiping Road,Beijing 100850,China. | 2005 | Cellular & Molecular Immunology2005，2，6： | 2 |
| 9 | Active regions' setting of the extracellular ligand-binding domain of human interleukin-6 receptor显示文摘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. | Yunfang Ren Hong Qu Jiannan Feng Song Li Beifen Shen | 2000 | Chinese Science Bulletin2000，45，13： | 2 |
| 10 | Identification of binding epitope of a monoclonal antibody (Z12) against human TNF-α using computer modeling and deletion mutant technique显示文摘The genes of the heavy and light chain variable region (VH, VL) of Z12 antibody against hTNF-a were cloned, and according to the translated sequence of amino acids, the spa-tial structures of VH and VL domains were modeled by using homology-based modeling method, followed by constructing the whole three-dimensional structure of Fv fragment. The complex model of Fv interacting with hTNF-a was gained with computer-guided molecular docking method, based on which, it was predicted that the epitope recognized by Z12 was from 141 to 146 of hTNF-a. hTNF-a molecule was divided into two fragments of N-terminal region from 1 to 91 and C-terminal region from 92 to 157 with prokaryotic expression. The measured results suggested that the antigenic epitope recognized by Z12 antibody was located in the C-terminal region 92-157 of hTNF-a, proving the predicted result reliable preliminarily. Further experimental results showed that after hTNF- 141-146 residues were deleted, Z12 antibody almost lost the ability to recognize the mutant, suggesting that the amino acid residues from 141 to 146 of hTNF-a were specially recognized by Z12 antibody. | ZHANG Wei FENG Jiannan SHEN Beifen | 2004 | Science China(Life Sciences)2004，47，3： | 2 |
| 11 | SHP limits TLR signaling, an inducible transcriptional corepressor显示文摘Toll-like receptor(TLR)signaling stimulated by diverse microbial components plays a pivotal role in innate immunity by eliciting a powerful proinflammatory response that is essential for pathogen elimination.However,uncontrolled inflammation can result in tissue damage.Thus,TLR signaling has to be tightly controlled to maintain immune balance in the organism.The paradigm for modulating TLR signaling seems to center on the canonical nuclear factor-kB(NF-kB)pathway,most likely because of the central role of NF-kB in the production of various proinflammatory cytokines.1 In a recent issue of Nature Immunology,Yuk et al.have reported the identification of a novel endogenous NF-kB inhibitor in TLR signaling—small heterodimer partner(SHP)2 Interestingly,SHP functions in a self-regulating system:TLR signaling induces the expression of SHP in macrophages through Ca21-dependent activation of AMP-activated protein kinase(AMPK),which has anti-inflammatory effects3 SHP in turn decreases the expression of proinflammatory cytokines such as tumor necrosis factor-a(TNF-a)by physically binding to two key components of the canonical NF-kB pathway,namely,RelA/p65 and TNF receptorassociated factor 6(TRAF6)This work demonstrates an essential role for SHP in the negative control of TLR signaling and provides a novel underlying molecular mechanism. | Jiyan Zhang Beifen Shen | 2011 | Cellular & Molecular Immunology2011，8，6： | 1 |
| 12 | C-terminus of TRAP in Staphylococcus can enhance the activity of lysozyme and lysostaphin显示文摘在葡萄球菌 aureus,激活蛋白质(陷井) 的 RNAIII 的目标是其 C 终点能被用作一支疫苗对 staphylococcal 感染提供保护的联系膜的蛋白质。这里,我们由表面电浆子第一次证明回声和套住的连接酶的 immunosorbent 试金能明确地通过它的 C 终点(氨基酸 155-167 ) 绑溶解酵素和 lysostaphin 并且在 vitro 提高 lysozomal 活动。陷井异种紧张对 lysostaphin 更抵抗比,这也被发现野类型。我们的以前的数据证明陷井力量的 C 终点是细胞外的。我们的结果因此建议陷井的 C 终点能对 S 作为 lysozyme/lysostaphin 的特定的指向蛋白质起作用。aureus 房间墙和相互作用的生物意义可能是便于 lysozyme/lysostaphin-mediated 房间细胞溶解。 | Guang Yang Yaping Gao Jiannan Feng Yong Huang Shaohua Li Yu Liu Chuan Liu Ming Fan Beifen Shen Ningsheng Shao | 2008 | Acta Biochimica et Biophysica Sinica2008，40，5： | 1 |
| 13 | Identification of the RNA chaperone activity of recombinant human tumor necrosis factor alpha in vitro显示文摘 | Guojun Cao Guang Yang Zhaohui Liu Xuemei Liu Jie Zhang Dajin Zhang Nongle Liu Hongmei Ding Ming Fan Beifen Shen Ningsheng Shao | 2005 | Biochemical and Biophysical Research Communications2005，，2： | 1 |
| 14 | The N- and C-terminal carbohydrate recognition domains of galectin-9 contribute differently to its multiple functions in innate immunity and adaptive immunity显示文摘 | Yurong Li Jiannan Feng Shaoxia Geng Shusheng Geng Huawei Wei Guojiang Chen Xinying Li Liyan Wang Renxi Wang Hui Peng Gencheng Han Beifen Shen Yan Li | 2010 | Molecular Immunology2010，，4： | 1 |
| 15 | Biosynthesis of rumbrins and inspiration for discovery of HIV inhibitors显示文摘Investigation on how nature produces natural compounds with chemical and biological diversity at the genetic level offers inspiration for the discovery of new natural products and even their biological targets.The polyketide rumbrin(1)is a lipid peroxide production and calcium accumulation inhibitor,which contains a chlorinated pyrrole moiety that is a rare chemical feature in fungal natural products.Here,we identify the biosynthetic gene cluster(BGC)rum of 1 and its isomer 12E-rumbrin(2)from Auxarthron umbrinum DSM3193,and elucidate their biosynthetic pathway based on heterolo-gous expression,chemical complementation,and isotopic labeling.We show that rumbrins are assembled by a highly reducing polyketide synthase(HRPKS)that uniquely incorporates a proline-derived pyrrolyl-CoA starer unit,and followed by methylation and chlorination.Sequent precursor directed biosynthesis was able to yield a group of rumbrin analogues.Remarkably,inspired by the presence of a human immunodeficiency virus(HIV)-Nef associated gene in the rum cluster,we predicted and pharmacologically demonstrated rumbrins as potent inhibitors of HIV at the nanomolar level.This work enriches the recognition of unconventional starter units of fungal PKSs and provides a new strategy for genome mining-guided drug discovery. | Beifen Zhong Jun Wan Changhui Shang Jiajia Wen Yujia Wang Jian Bai Shan Cen Youcai Hu | 2022 | Acta Pharmaceutica Sinica B2022，12，11： | 1 |
| 16 | A Novel Neutralizing Monoclonal Antibody against Cell-binding polypeptide of Ricin 显示文摘 | Jianwei Guo Beifen Shen Jiannan Feng | 2005 | Hybridoma2005，24，5： | 1 |
| 17 | Human IgG1 C_γ1 Domain Is Crucial for the Bioactivity of the Engineered Anti-CD20 Antibodies显示文摘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. | Shusheng Geng Jiannan Feng Yan Li Xianjiang Kang Yingxun Sun Xin Gu Ying Huang Hong Chang Beifen Shen | 2007 | Cellular & Molecular Immunology2007，4，2： | 1 |
| 18 | Modulation of IFN-γ Receptor 1 Expression by AP-2α Influences IFN-γ Sensitivity of Cancer Cells显示文摘 | Changguo Chen Liang Guo Ming Shi Ming Hu Meiru Hu Ming Yu Tianyou Wang Lun Song Beifen Shen Lu Qian Ning Guo | 2012 | The American Journal of Pathology2012，，： | 1 |
| 19 | High-Affinity Decoy PD-1 Mutant Screened from an Epitope-Specific Cell Library显示文摘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. | Hao Liu Chunxia Qiao Naijing Hu Zhihong Wang Jing Wang Jiannan Feng Beifen Shen Yuanfang Ma Longlong Luo | 2021 | Engineering2021，7，11： | 0 |
| 20 | A Novel Human Antibody,HF,against HER2/erb-B2 Obtained by a Computer-Aided Antibody Design Method显示文摘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. | Chunxia Qiao Ming Lv Xinying Li Xiaoling Lang Shouqin Lv Mian Long Yan Li Shusheng Geng Zhou Lin Beifen Shen Jiannan Feng | 2021 | Engineering2021，7，11： | 0 |
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