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Science China(Life Sciences) 2004年第3期47卷 279-286页

作者： ZHANG Wei feng jiannan SHEN Beifen Beijing Basic Medical Institute Beijing 100850 China Beijing Basic Medical Institute Beijing 100850 China Beijing Basic Medical Institute Beijing 100850 China

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.

关键词： human tumor necrosis factor-α, Fv, antigenic epitope, homology-based modeling, deletion.

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.

Identification and characterization of mammaglobin-A epitope in heterogenous breast cancers for enhancing tumor-targeting therapy

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Signal Transduction and Targeted Therapy 2020年第1期5卷 1778-1788页

作者： Zhiqiang Liu Xiqin Yang Cuimi Duan Jiangxue Li Rongsheng Tong Yuting Fan jiannan feng Ruiyuan Cao Wu Zhong Xiaoyan feng Heqiu Zhang Lulu Cai Beijing Institute of Basic Medical Sciences 27 Taiping RoadHaidian DistrictBeijing 100850China Personalized Drug Therapy Key Laboratory of Sichuan Province Department of PharmacySichuan Provincial People’s HospitalUniversity of Electronic Science and Technology of ChinaChengdu 611731China Beijing Institute of Pharmacology and Toxicology 27 Taiping RoadHaidian DistrictBeijing 100850China

Although targeted therapy has been extensively investigated for breast cancers,a molecular target with broad application is currently unavailable due to the high heterogeneity of these ***-A(Mam-A),which is overexpressed in most breast carcinomas,has been proposed as a promising ***,the lack of specific targeting moieties due to uncertain binding epitopes hampers further translational ***,seven potential epitopes of Mam-A were disclosed,and a unique epitope was then identified in most types of breast cancers,despite the genotypic *** phage display technology,the epitope was determined to be N-terminal amino acids 42–51 of Mam-A(N42–51).Then,the N42–51 epitope-specific monoclonal antibody,mAb785,was conjugated to poly lactic-co-glycolic acid(PLGA)nanoparticles loaded with therapeutic agents,thereby enhancing the drug uptake and therapeutic efficacy in different genotypes of breast *** computer simulation of the N42–51 epitope and the mAb785 structures,as well as their interactions,further revealed the specific targeting mechanism of the mAb785-conjugated nanoparticles to breast cancers.

关键词： breast cancers epitope

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 *** PD-1/PD-L1 pathway inhibits T cell activation in the micro-environment,making it an attractive target against ***-type(WT)PD-1 ectodomain has been shown to have difficulty blocking PD-1/PD-L1 mixture formation due to its low *** present work uses three-dimensional(3D)crystal complex structures to analyze the interaction by which PD-1 binds to PD-L1 or *** also reports on a theoretical study of the binding mode between PD-1 and its clinical antibody *** 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 *** 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 *** 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 *** interestingly,an even lower dose of 463(2 mg·kg^(-1))showed a better effect than 10 mg·kg^(-1) of WT *** 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

Antioxidant properties and sensory evaluation of microgreens from commercial and local farms

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Food Science and Human Wellness 2020年第1期9卷 45-51页

作者： Libo Tan Holly Nuffer jiannan feng Shu Hang Kwan Hsiangting Chen Xiao Tong Lingyan Kong Department of Human Nutrition and Hospitality Management University of AlabamaTuscaloosaAL 35487USA Department of Clothing Textile&Interior DesignUniversity of AlabamaTuscaloosaAL 35487USA

Microgreens are young and tender vegetables or herbs that provide attractive color,flavor,and *** purpose of this study was to evaluate the nutritional and sensory qualities of broccoli microgreens grown by different methods(hydroponically *** grown)and from different sources(commercial *** farm).No significant difference in total phenolic concentration and antioxidant capacity was found in all broccoli microgreens,but a significantly higher chlorophyll concentration was found in farm microgreens than the commercial ***,the soil-grown farm microgreens possessed a significantly higher vitamin C concentration than hydroponically-grown farm sample and commercial *** in the sensory study favored farm samples regardless of growing method,and their overall liking was significantly correlated with taste of the *** addition,six other microgreens from the local farm were analyzed for their nutritional *** conclusions suggested a potential for consumers to still benefit nutritionally by purchasing commercial microgreens at a lower cost;however,it may be worthwhile for consumers to purchase microgreens from local farms for a better sensory experience.

关键词： Microgreens Antioxidant Phenolic Chlorophyll Sensory Hydroponics

Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission

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Science China(Life Sciences) 2020年第3期63卷 457-460页

作者： Xintian Xu Ping Chen Jingfang Wang jiannan feng Hui Zhou Xuan Li Wu Zhong Pei Hao Key Laboratory of Molecular Virology and Immunology Institut Pasteur of ShanghaiCenter for Biosafety Mega-ScienceChinese Academy of SciencesShanghai 200031China Key Laboratory of Synthetic Biology CAS Center for Excellence in Molecular Plant SciencesChinese Academy of SciencesShanghai 200032China Key Laboratory of Systems Biomedicine Ministry of EducationShanghai Center for Systems BiomedicineShanghai Jiao Tong UniversityShanghai 200240China National Engineering Research Center for the Emergence Drugs Beijing Institute of Pharmacology and ToxicologyBeijing 100850China The Joint Program in Infection and Immunity:a.Guangzhou Women and Children’s Medical Center Guangzhou Medical UniversityGuangzhou 510623China The Joint Program in Infection and Immunity Institute Pasteur of ShanghaiChinese Academy of SciencesShanghai 200031China

Dear Editor,The occurrence of concentrated pneumonia cases in Wuhan city,Hubei province of China was first reported on December 30,2019 by the Wuhan Municipal Health Commission(WHO,2020).The pneumonia cases were found to be linked to a large seafood and animal market in Wuhan,and measures for sanitation and disinfection were taken swiftly by the local government *** Centers for Disease Control and Prevention(CDC)and Chinese health authorities later determined and announced that a novel coronavirus(CoV),denoted as 2019-nCoV,had caused the pneumonia outbreak in Wuhan city(CDC,2020).Scientists from multiple groups had obtained the virus samples from hospitalized patients(Normile,2020).The isolated viruses were morphologically identical when observed under electron microscopy.

关键词： Wuhan Evolution measures

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

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 *** present,most potential antibody drugs in clinical trials are humanized or fully *** 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 ***,we describe a structure-based computer-aided de novo design technology for human antibody *** 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 ***,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 *** 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

Binding Activity Difference of Anti-CD20 scFv-Fc Fusion Protein Derived from Variable Domain Exchange

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Cellular & Molecular Immunology 2006年第6期3卷 439-443页

作者： Shusheng Geng jiannan feng Yan Li Yingxun Sun Xin Gu Ying Huang Yugang Wang Xianjiang Kang Hong Chang Beifen Shen College of Life Science Hebei University Baoding Hebei China Institute of Basic Medical Sciences Beijing China Lab of Cellular and Molecular Immunology Medical School of Henan University Kaifeng Henan China These authors contributed equally to this work

Two novel engineered antibody fragments binding to antigen CD20 were generated by fusing a murine IgM-type anti-CD20 singie-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.

关键词： binding activity scFv-Fc variable domain exchange molecular modeling

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 *** obtained a novel anti-human programmed death 1(PD-1)antibody using computer-aided design and a mammalian cell display technology *** 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 ***,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 *** 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 *** virtual antibody libraries were displayed on the surface of mammalian cells as the antigen-binding fragments of full-length immunoglobulin ***,we used flow cytometry and sequencing approaches to sort and screen the ***,we obtained a novel anti-human PD-1 antibody named ***78 competitively recognized the PD-1 epitopes that interacted with MIL75 and possessed an affinity comparable to *** 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