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Mutational escape prevention by combination of four neutralizing antibodies that target RBD conserved regions and stem helix

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Virologica Sinica 2022年第6期37卷 860-873页

作者： Haoneng Tang Yong Ke Yunji Liao Yanlin Bian yunsheng yuan Ziqi Wang Li Yang Hang Ma Tao Sun Baohong Zhang Xiaoju Zhang Mingyuan Wu Jianwei Zhu Engineering Research Center of Cell and Therapeutic Antibody Ministry of EducationShanghai200240China School of Pharmacy Shanghai Jiao Tong UniversityShanghai200240China Department of Respiratory and Critical Care Medicine Zhengzhou University People's Hospital/Henan Provincial People's HospitalZhengzhou450003China School of Agriculture and Biology Shanghai Jiao Tong UniversityShanghai200240China Shanghai Municipal Veterinary Key Laboratory Shanghai200240China Jecho Institute Shanghai200240China

New variants of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) appear rapidly every few *** have showed powerful adaptive ability to circumvent the immune system. To further understand SARS-CoV-2’s adaptability so as to seek for strategies to mitigate the emergence of new variants, herein we investigated the viral adaptation in the presence of broadly neutralizing antibodies and their combinations. First, we selected four broadly neutralizing antibodies, including pan-sarbecovirus and pan-betacoronavirus neutralizing antibodies that recognize distinct conserved regions on receptor-binding domain(RBD) or conserved stem-helix region on S2 *** binding competition analysis, we demonstrated that they were capable of simultaneously ***, a replication-competent vesicular stomatitis virus pseudotyped with SARS-CoV-2 spike protein was employed to study the viral adaptation. Twenty consecutive passages of the virus under the selective pressure of individual antibodies or their combinations were performed. It was found that it was not hard for the virus to adapt to broadly neutralizing antibodies, even for pan-sarbecovirus and pan-betacoronavirus antibodies. The virus was more and more difficult to escape the combinations of two/three/four antibodies. In addition, mutations in the viral population revealed by high-throughput sequencing showed that under the selective pressure of three/four combinational antibodies, viral mutations were not prone to present in the highly conserved region across betacoronaviruses(stem-helix region), while this was not true under the selective pressure of single/two ***, combining neutralizing antibodies targeting RBD conserved regions and stem helix synergistically prevented the emergence of escape mutations. These studies will guide future vaccine and therapeutic development efforts and provide a rationale for the design of RBD-stem helix tandem vaccine, which may help to impede

关键词： SARS-CoV-2 Adaptation Spike protein Stem helix Broadly neutralizing antibody

Characterization of a novel bispecific antibody targeting tissue factor-positive tumors with T cell engagement

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1928-1942页

作者： Zhidi Pan Jie Chen Xiaodong Xiao Yueqing Xie Hua Jiang Baohong Zhang Huili Lu yunsheng yuan Lei Han Yuexian Zhou Huifang Zong Lei Wang Rui Sun Jianwei Zhu Engineering Research Center of Cell&Therapeutic Antibody MOESchool of PharmacyShanghai Jiao Tong UniversityShanghai 200240China Jecho Laboratories Inc.FrederickMD 21704USA Jecho Biopharmaceuticals Co. Ltd.Tianjin 300467China

T cell engaging bispecific antibody(TCB)is an effective immunotherapy for cancer *** co-targeting CD3 and tumor-associated antigen(TAA),TCB can redirect CD3+T cells to eliminate tumor cells regardless of the specificity of T cell *** factor(TF)is a TAA that involved in tumor ***,we designed and characterized a novel TCB targeting TF(TF-TCB)for the treatment of TF-positive *** vitro,robust T cell activation,tumor cell lysis and T cell proliferation were induced by *** tumor cell lysis activity was dependent upon both CD3 and TF binding moieties of the TF-TCB,and was related to TF expression level of tumor *** vivo,in both tumor cell/human peripheral blood mononuclear cells(PBMC)co-grafting model and established tumor models with poor T cell infiltration,tumor growth was strongly inhibited by TF-TCB.T cell infiltration into tumors was induced during the ***,efficacy of TF-TCB was further improved by combination with immune checkpoint *** the first time,our results validated the feasibility of using TF as a target for TCB and highlighted the potential for TF-TCB to demonstrate efficacy in solid tumor treatment.

关键词： T cell engaging bispecific antibody Immunotherapy Tissue factor Solid tumor Pancreatic cancer Lung cancer PD-1 antibody

Neutralization of SARS-CoV-2 infection by antibodies targeting diverse epitopes

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Genes & Diseases 2024年第4期11卷 134-137页

作者： Shusheng Wang Yunji Liao Kaiyong Yang Hang Ma Zhangyi Song Haiqiu Huang Li Zhang Ailing Wang Lei Han Jiawei Zhang Hui Chen Haiyang Yin Yantin Bian Hua Jiang Xiaodong Xiao Yueqing Xie yunsheng yuan Jianwei Zhu Engineering Research Center of Cell and Therapeutic Antibody Ministry of EducationSchool of PharmacyShanghai Jiao Tong UniversityShanghai 200240China Jecho Laboratories Inc.FrederickMD 21704USA Jecho Institute Co. Ltd.Shanghai 200240China

The CoVID-19 pandemic that started in late 2019 is sweeping through the world,posing historic challenges to global health,and disrupting social and economic *** and recent studies indicate that monoclonal antibodies can be efficacious in preventing and treating SARSCoV-1 and SARS-CoV-2 *** a phage display platform,we have identified dozens of monoclonal antibodies that bind to diverse epitope groups on the SARS-CoV-2 spike *** of them bound to the receptor binding domain(RBD)and inhibited ACE2-RBD interaction.

关键词： antibodies inhibited monoclonal

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mRNA疫苗生产厂房工艺工程设计探索

中国医药工业杂志 2022年第12期53卷 1796-1802,1819页

作者：黄洁袁运生上海交通大学药学院教育部细胞工程及抗体药物工程研究中心上海200240

mRNA疫苗技术作为最新一代的疫苗制备技术已实现疫苗生产和临床应用,例如新型冠状病毒肺炎mRNA疫苗(COVID-19 mRNA vaccine)。和传统的灭活疫苗、重组亚单位疫苗相比,mRNA疫苗技术具有效价高、开发周期短、安全性好、生产技术通用性高... 详细信息

mRNA疫苗技术作为最新一代的疫苗制备技术已实现疫苗生产和临床应用,例如新型冠状病毒肺炎mRNA疫苗(COVID-19 mRNA vaccine)。和传统的灭活疫苗、重组亚单位疫苗相比,mRNA疫苗技术具有效价高、开发周期短、安全性好、生产技术通用性高的特点。由于mRNA的特点和工艺特殊性,传统的生物药物设计理念已经不能完全符合其制备要求,如何合理设计mRNA疫苗生产厂房和工艺工程是值得研究的问题。由于各国的地理位置、人文特点、能源结构、环保要求等都各不相同,因此在借鉴欧美已有的mRNA疫苗规模化生产设施的基础上,该研究探索了符合我国国情的生产设施和工艺工程设计方案,并以拟定的目标生产规模(每年10亿剂次量)进行产能计算及分析,探索了mRNA疫苗大规模商业化生产厂房的工艺工程设计要点,阐述并讨论了厂房平面布局、洁净区域划分、人流和物流走向、压差分布和气流方向等,以期为国内mRNA疫苗商业化生产平台的快速落地提供参考。

关键词： mRNA疫苗生产设施工艺工程设计 GMP

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袁运生绘画

文化艺术研究 2022年第4期15卷 I0002-I0013,F0003页

作者：袁运生中央美术学院中国古代造型研究中心

重组人白细胞介素-1受体拮抗剂对急性肝衰竭小鼠肝脏保护作用的评价

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中国医药工业杂志 2019年第3期50卷 320-324页

作者：朱晨岑郑滢肖欣怡朱建伟袁运生细胞工程及抗体药物教育部工程研究中心上海交通大学药学院上海200240

采用(+)-D-氨基半乳糖盐酸盐(D-Ga1N)结合脂多糖(LPS)诱导小鼠急性肝衰竭(AHF)来评价重组人白细胞介素-1受体拮抗剂(rhIL-1Ra)对肝脏的保护作用。本研究用SPF级雄性C57BL/6小鼠建立AHF模型。造模前1 h,小鼠腹腔注射3、9 mg/kg的rhIL-1R... 详细信息

采用(+)-D-氨基半乳糖盐酸盐(D-Ga1N)结合脂多糖(LPS)诱导小鼠急性肝衰竭(AHF)来评价重组人白细胞介素-1受体拮抗剂(rhIL-1Ra)对肝脏的保护作用。本研究用SPF级雄性C57BL/6小鼠建立AHF模型。造模前1 h,小鼠腹腔注射3、9 mg/kg的rhIL-1Ra或等体积的生理盐水(NS),注射造模药物后4 h采集小鼠血液和肝组织样本。分析各组小鼠循环中的谷丙转氨酶(ALT)、谷草转氨酶(AST)、总胆红素(TBIL)水平和肝组织切片,并用荧光定量PCR方法分析肝组织中一氧化氮合成酶2(NOS2)和白细胞介素-6(IL-6)的表达水平变化。本研究还进一步通过死亡率试验考察rhIL-1Ra对AHF模型小鼠的保护作用。结果表明,9mg/kg剂量的rhIL-1Ra可以显著抑制AHF模型小鼠循环中的ALT和AST活性以及TBIL水平,减轻肝组织坏死和肝细胞变性程度,降低肝组织中NOS2和IL-6的表达。2个剂量(3和9mg/kg)的rhIL-1Ra都可以显著地改善AHF模型小鼠的生存率。结果表明,rhIL-1Ra在AHF药物开发和临床应用中具有潜在价值。

关键词：急性肝衰竭重组人白细胞介素-1 受体拮抗剂谷丙转氨酶谷草转氨酶一氧化氮合成酶2 白细胞介素-6 生存率

应用Cre-loxP系统构建肝组织特异性ATF5基因敲除小鼠模型

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中国医药工业杂志 2021年第12期52卷 1609-1614页

作者：白思益陈会帕梅拉·帕尔哈提邓晴朱建伟袁运生上海交通大学药学院教育部细胞工程及抗体药物工程研究中心上海200240

应用Cre-loxP重组酶系统构建肝组织特异性ATF5基因敲除小鼠(ATF5^(Flox/Flox)-Alb-Cre^(+/-))模型。采用Alb-Cre工具鼠,用带有Cre-loxP系统的ATF5 Flox纯合子小鼠(ATF5^(Flox/Flox))和带有Alb-Cre杂合子(Alb-Cre^(+/-))的转基因小鼠进行杂交,对产生的子代利用实时荧光定量聚合酶链式反应(PCR)进行基因型鉴定。筛选出子代ATF5^(Flox/-)-Alb-Cre^(+/-)小鼠,其与ATF5^(Flox/Flox)小鼠进一步交配可获得ATF5^(Flox/Flox)-Alb-Cre^(+/-)小鼠,该基因型小鼠的肝细胞基因组中ATF5的外显子缺失。选取雌性、7~8周龄的ATF5^(Flox/Flox)-Alb-Cre^(+/-)和ATF5^(Flox/Flox)-Alb-Cre^(-/-)小鼠各3只,采用实时荧光定量PCR测定ATF5在肝、肾、心和脑组织中的表达量,并采用常规苏木精-伊红(HE)染色,观察2种小鼠各脏器的组织形态。结果表明,该系统可实现ATF5在肝脏中的特异性敲除,敲除效率可达到97%。此外,2种小鼠的肝、肾、肺、心和脑组织形态无明显改变,可为研究ATF5在肝脏中的生物学功能提供体内模型参考。

关键词：转录激活因子5 Cre-loxP重组酶系统组织特异性敲除基因型鉴定

Insights into Formation and Li-Storage Mechanisms of Hierarchical Accordion-Shape Orthorhombic CuNb_(2)O_(6) toward Lithium-Ion Capacitors as an Anode-Active Material

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Energy & Environmental Materials 2024年第2期7卷 287-298页

作者： Chao Cheng yunsheng Yan Minyu Jia Yang Liu Linrui Hou Changzhou yuan School of Material Science and Engineering University of JinanJinan 250022China

The orthorhombic CuNb_(2)O_(6)(O-CNO)is established as a competitive anode for lithium-ion capacitors(LICs)owing to its attractive compositional/structural ***,the high-temperature synthesis(>900℃)and controversial charge-storage mechanism always limit its ***,we develop a low-temperature strategy to fabricate a nano-blocks-constructed hierarchical accordional O-CNO framework by employing multilayered Nb_(2)CT_(x)as the niobium *** intrinsic stress-induced formation/transformation mechanism of the monoclinic CuNb_(2)O_(6)to O-CNO is tentatively put ***,the integrated phase conversion and solid solution lithium-storage mechanism is reasonably unveiled with comprehensive in(ex)situ *** to its unique structural merits and lithium-storage process,the resulted O-CNO anode is endowed with a large capacity of 150.3 mAh g^(-1)at 2.0 A g^(-1),along with long-duration cycling ***,the constructed O-CNO-based LICs exhibit a high energy(138.9 Wh kg^(-1))and power(4.0 kW kg^(-1))densities with a modest cycling stability(15.8%capacity degradation after 3000 consecutive cycles).More meaningfully,the in-depth insights into the formation and charge-storage process here can promote the extensive development of binary metal Nb-based oxides for advanced LICs.

关键词： high-rate anodes lithium-ion capacitors lithium-storage mechanisms orthorhombic CuNb_(2)O_(6) phase transform

Measurement of light polarization characteristics from an oil-polluted soil surface in near-infrared bands

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Chinese Science Bulletin 2009年第9期54卷 1607-1612页

作者： WANG yuan SHENG LianXi LI Ke ZHAO NaiZhuo ZHAO yunsheng College of Urban and Environmental Sciences Northeast Normal University Changchun 130024 China State Environmental Protection Key Laboratory of Wetland Ecology and Vegetation Restoration Northeast Normal Univesity Changchun 130024 China School of Municipal and Environmental Engineering Jilin Institute of Architecture and Civil Engineering Changchun 130021 China

Oil pollution can be monitored by infrared remote sensing technology. In this work, the degree of po-larization (DOP) was established as a quantitative index of oil pollution. The crude oil and the local typical surface soil from the Songyuan oil field in Jilin province were collected. Some soil samples with four levels of oil content and three levels of water content were prepared and measured. The DOP of the polluted soil and the clean soil in the field was also measured at 180° relative viewing azimuth angle, and 10°, 30° and 50° viewing zenith angles. It was found that with rising soil oil content, the DOP of the reflected light on the soil surface increased when the soil water content was low, and decreased when the soil water content was high.

关键词：土壤表面石油污染近红外波段光偏振特性测量土壤水分含量红外遥感技术定量指标