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Emerging immunological strategies: recent advances and future directions

《医学前沿(英文)》 2021年 第15卷 第6期   页码 805-828 doi: 10.1007/s11684-021-0886-x

摘要: Immunotherapy plays a compelling role in cancer treatment and has already made remarkable progress. However, many patients receiving immune checkpoint inhibitors fail to achieve clinical benefits, and the response rates vary among tumor types. New approaches that promote anti-tumor immunity have recently been developed, such as small molecules, bispecific antibodies, chimeric antigen receptor T cell products, and cancer vaccines. Small molecule drugs include agonists and inhibitors that can reach the intracellular or extracellular targets of immune cells participating in innate or adaptive immune pathways. Bispecific antibodies, which bind two different antigens or one antigen with two different epitopes, are of great interest. Chimeric antigen receptor T cell products and cancer vaccines have also been investigated. This review explores the recent progress and challenges of different forms of immunotherapy agents and provides an insight into future immunotherapeutic strategies.

关键词: cancer immunotherapy     bispecific antibodies     small molecules     chimeric antigen receptor T therapy     cancer vaccines    

Preclinical characterization and comparison between CD3/CD19 bispecific and novel CD3/CD19/CD20 trispecificantibodies against B-cell acute lymphoblastic leukemia: targeted immunotherapy for acute lymphoblastic

《医学前沿(英文)》 2022年 第16卷 第1期   页码 139-149 doi: 10.1007/s11684-021-0835-8

摘要: The CD19-targeting bispecific T-cell engager blinatumomab has shown remarkable efficacy in patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. However, several studies showed that blinatumomab has a short plasma half-life due to its low molecular weight, and thus its clinical use is limited. Furthermore, multiple trials have shown that approximately 30% of blinatumomab-relapsed cases are characterized by CD19 negative leukemic cells. Here, we design and characterize two novel antibodies, A-319 and A-2019. Blinatumomab and A-319 are CD3/CD19 bispecific antibodies with different molecular sizes and structures, and A-2019 is a novel CD3/CD19/CD20 trispecific antibody with an additional anti-CD20 function. Our in vitro, ex vivo, and in vivo experiments demonstrated that A-319 and A-2019 are potent antitumor agents and capable of recruiting CD3 positive T cells, enhancing T-cell function, mediating B-cell depletion, and eventually inhibiting tumor growth in Raji xenograft models. The two molecules are complementary in terms of efficacy and specificity profile. The activity of A-319 demonstrated superior to that of A-2019, whereas A-2019 has an additional capability to target CD20 in cells missing CD19, suggesting its potential function against CD19 weak or negative CD20 positive leukemic cells.

关键词: B-cell acute lymphoblastic leukemia     bispecific antibody     trispecific antibody     CD19     CD20    

Broadly neutralizing antibodies and vaccine design against HIV-1 infection

Qian Wang, Linqi Zhang

《医学前沿(英文)》 2020年 第14卷 第1期   页码 30-42 doi: 10.1007/s11684-019-0721-9

摘要: Remarkable progress has been achieved for prophylactic and therapeutic interventions against human immunodeficiency virus type I (HIV-1) through antiretroviral therapy. However, vaccine development has remained challenging. Recent discoveries in broadly neutralizing monoclonal antibodies (bNAbs) has led to the development of multiple novel vaccine approaches for inducing bNAbs-like antibody response. Structural and dynamic studies revealed several vulnerable sites and states of the HIV-1 envelop glycoprotein (Env) during infection. Our review aims to highlight these discoveries and rejuvenate our endeavor in HIV-1 vaccine design and development.

关键词: HIV-1     broadly neutralizing antibodies     Env conformational states     vaccine design     SOSIP    

提升疗效的修饰型治疗性抗体国内外研究进展 Review

戴济民, 张雪芹, 戴竞耀, 杨向民, 陈志南

《工程(英文)》 2021年 第7卷 第11期   页码 1529-1540 doi: 10.1016/j.eng.2020.06.030

摘要:

生物治疗药物市场的繁荣反映了治疗性抗体药物用于治疗癌症、炎性疾病和难治性感染的可行性和有效性。随着抗体药物临床试验和转化研究中出现的结合效率不高、效应功能降低和不良反应频发等问题的解决,治疗性抗体的修饰在抗体药物的研发进程中得到了前所未有的蓬勃发展。为了提升抗体的结合活性、循环中的半衰期、靶细胞的有效性,并最终实现改善抗体药物的疗效,抗体可主要通过以下途径修饰:①糖基化修饰;②抗体恒定区(Fc)改造;③抗体亚类重构;④构建抗体-药物偶联物(ADC);⑤基于单链可变区片段(scFv)的嵌合抗原受体T细胞(CAR-T);⑥双特异性抗体(bsAb)。过去几十年来全球在修饰型治疗性抗体的领域取得了许多成就,中国作为对于生物治疗药物需求巨大并且拥有巨大研发潜力的国家在该领域亦发挥了积极作用。本文概括了修饰型治疗性抗体在当前国际研究中取得的进展,并在单独的章节中重点介绍了中国在该领域取得的成果。

关键词: 治疗性抗体     抗体修饰     疗效     抗原     抗体-药物偶联物     双特异性抗体    

Human monoclonal antibodies as candidate therapeutics against emerging viruses

null

《医学前沿(英文)》 2017年 第11卷 第4期   页码 462-470 doi: 10.1007/s11684-017-0596-6

摘要:

The emergence of new pathogens, such as severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and Ebola virus, poses serious challenges to global public health and highlights the urgent need for novel antiviral approaches. Monoclonal antibodies (mAbs) have been successfully used to treat various diseases, particularly cancer and immunological disorders. Antigen-specific mAbs have been isolated using several different approaches, including hybridoma, transgenic mice, phage display, yeast display, and single B-cell isolation. Consequently, an increasing number of mAbs, which exhibit high potency against emerging viruses in vitro and in animal models of infection, have been developed. In this paper, we summarize historical trends and recent developments in mAb discovery, compare the advantages and disadvantages of various approaches to mAb production, and discuss the potential use of such strategies for the development of antivirals against emerging diseases. We also review the application of recently developed human mAbs against SARS-CoV, MERS-CoV, and Ebola virus and discuss prospects for the development of mAbs as therapeutic agents against emerging viral diseases.

关键词: human monoclonal antibodies     emerging infectious diseases     SARS-CoV     MERS-CoV     Ebola virus    

Recent advances in “universal” influenza virus antibodies: the rise of a hidden trimeric interface in

Yulu Wang, Dan Hu, Yanling Wu, Tianlei Ying

《医学前沿(英文)》 2020年 第14卷 第2期   页码 149-159 doi: 10.1007/s11684-020-0764-y

摘要: Influenza causes seasonal outbreaks yearly and unpredictable pandemics with high morbidity and mortality rates. Despite significant efforts to address influenza, it remains a major threat to human public health. This issue is partially due to the lack of antiviral drugs with potent antiviral activity and broad reactivity against all influenza virus strains and the rapid emergence of drug-resistant variants. Moreover, designing a universal influenza vaccine that is sufficiently immunogenic to induce universal antibodies is difficult. Some novel epitopes hidden in the hemagglutinin (HA) trimeric interface have been discovered recently, and a number of antibodies targeting these epitopes have been found to be capable of neutralizing a broad range of influenza isolates. These findings may have important implications for the development of universal influenza vaccines and antiviral drugs. In this review, we focused on the antibodies targeting these newly discovered epitopes in the HA domain of the influenza virus to promote the development of universal anti-influenza antibodies or vaccines and extend the discovery to other viruses with similar conformational changes in envelope proteins.

关键词: influenza virus     neutralizing antibody     hemagglutinin     globular head region     trimeric interface    

Synthesis of haptens and production of antibodies to bisphenol A

Xiya ZHANG, Xiaoyun DONG, Sijun ZHAO, Yuebin KE, Kai WEN, Suxia ZHANG, Zhanhui WANG, Jianzhong SHEN

《农业科学与工程前沿(英文)》 2017年 第4卷 第3期   页码 366-372 doi: 10.15302/J-FASE-2017132

摘要: Three immunizing haptens of bisphenol A (BPA), including two new haptens, were used to produce highly sensitive and specific polyclonal antibodies. The spacer arms of haptens for coupling to the protein carrier were located at different positions in BPA, and different length spacer arms were tested. Highly sensitive polyclonal antibodies were obtained and characterized using indirect competitive enzyme-linked immunosorbent assay (icELISA). Under optimized conditions, the half maximal inhibitory concentration (IC ) value of the best polyclonal antibody was 2.1 mg·L , based on coating heterogeneous antigens, and this optimal polyclonal antibody was highly sensitive toward BPA and displayed negligible cross-reactivity with bisphenol B and bisphenol E. A sensitive icELISA method utilizing the polyclonal antibody was developed for the determination of BPA in milk. In spiked samples (5, 10 and 20mg·L ), the recovery ranged from 80% to 102% with a coefficient of variation (CV) value below 15.8%. The limit of detection of icELISA was 1.95mg·L . These results indicate that the icELISA method is suitable for the detection of BPA in milk.

关键词: bisphenol A     cross-reactivity     hapten     indirect competitive ELISA     polyclonal antibody    

Durability of neutralizing antibodies and T-cell response post SARS-CoV-2 infection

Yun Tan, Feng Liu, Xiaoguang Xu, Yun Ling, Weijin Huang, Mingquan Guo, Ziyu Fu, Dongguo Liang, Miao Xu, Hongzhou Lu, Saijuan Chen

《医学前沿(英文)》 2020年 第14卷 第6期   页码 746-751 doi: 10.1007/s11684-020-0822-5

摘要: The ongoing pandemic of coronavirus disease 19 (COVID-19) is caused by a newly discovered β coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). How long the adaptive immunity triggered by SARS-CoV-2 can last is of critical clinical relevance in assessing the probability of second infection and efficacy of vaccination. Here we examined, using ELISA, the IgG antibodies in serum specimens collected from 17 COVID-19 patients at 6−7 months after diagnosis and the results were compared to those from cases investigated 2 weeks to 2 months post-infection. All samples were positive for IgGs against the S- and N-proteins of SARS-CoV-2. Notably, 14 samples available at 6−7 months post-infection all showed significant neutralizing activities in a pseudovirus assay, with no difference in blocking the cell-entry of the 614D and 614G variants of SARS-CoV-2. Furthermore, in 10 blood samples from cases at 6−7 months post-infection used for memory T-cell tests, we found that interferon γ-producing CD4 and CD8 cells were increased upon SARS-CoV-2 antigen stimulation. Together, these results indicate that durable anti-SARS-CoV-2 immunity is common in convalescent population, and vaccines developed from 614D variant may offer protection from the currently predominant 614D variant of SARS-CoV-2.

关键词: SARS-CoV-2     neutralizing antibodies     T-cell response    

Characterization of polyclonal antibodies against nonstructural protein 9 from the porcine reproductive

Mengmeng ZHAO,Juanjuan QIAN,Jiexiong XIE,Tiantian CUI,Songling FENG,Guoqiang WANG,Ruining WANG,Guihong ZHANG

《农业科学与工程前沿(英文)》 2016年 第3卷 第2期   页码 153-160 doi: 10.15302/J-FASE-2016097

摘要: Porcine reproductive and respiratory syndrome (PRRS) is considered to be one of the most important infectious diseases impacting the swine industry and is characterized by reproductive failure in late term gestation in sows and respiratory disease in pigs of all ages. The nonstructural protein 9 gene, , encoding the RNA-dependent RNA polymerase, is generally regarded as fairly conserved when compared to other viral proteins. Antibodies against 9 will be of great importance for the diagnosis and treatment of the causal agent, PRRS virus. A study was undertaken to generate polyclonal antibodies against the immunodominant 9. For this purpose, the 9 was expressed in and subsequently used as an antigen to immunize New Zealand rabbits. Antiserum was identified via an indirect ELISA, and then verified based on the ability to react with both naturally and artificially expressed 9. Results of virus neutralization test showed that this antiserum could not neutralize the PRRSV. Nevertheless, this antiserum as a diagnostic core reagent should prove invaluable for further investigations into the mechanism of PRRS pathogenesis.

关键词: PRRSV     Nsp9     expression     antibody     neutralize    

The biopharmaceutical industry in China: history and future perspectives

null

《医学前沿(英文)》 2012年 第6卷 第2期   页码 101-111 doi: 10.1007/s11684-012-0191-9

摘要:

Biopharmaceuticals reflect the rapid progress achieved in modern biomedical research. This area has also become one of the main criteria for assessing the development level of biotechnology for a particular country. Although it has been only three decades since the first biopharmaceutical, recombinant human insulin, was licensed by the US Food and Drug Administration, the biopharmaceutical industry has become the fastest growing, most dynamic and technology-intensive sector in the biomedical field. Since the licensing of recombinant human interferon α1b in 1989, the biopharmaceutical industry in China has gone through initial developments and gradually entered a period of rapid growth. This paper provides an overview of the status and development trends of biopharmaceuticals in China, and compares them with those observed in developed countries.

关键词: biopharmaceuticals     antibodies     market trends     diseases     China     national regulatory agency    

Anti-β glycoprotein I antibodies in complex with β2 glycoprotein I induce platelet activation via two

null

《医学前沿(英文)》 2016年 第10卷 第1期   页码 76-84 doi: 10.1007/s11684-015-0426-7

摘要:

Anti-β2 glycoprotein I (anti-β2GP I ) antibodies are important contributors to thrombosis, especially in patients with antiphospholipid syndrome (APS). However, the mechanism by which anti-β2GP I antibodies are involved in the pathogenesis of thrombosis is not fully understood. In this report, we investigated the role of anti-β2GP I antibodies in complexes with β2GP I as mediators of platelet activation, which can serve as a potential source contributing to thrombosis. We examined the involvement of the apolipoprotein E receptor 2' (apoER2') and glycoprotein I ba (GP I bα) in platelet activation induced by the anti-β2GP I /β2GP I complex. The interaction between the anti-β2GP I /β2GP I complex and platelets was examined using in vitro methods, in which the Fc portion of the antibody was immobilized using protein A coated onto a microtiter plate. Platelet activation was assessed by measuring GP II b/ III a activation and P-selectin expression and thromboxane B2 production as well as p38 mitogen-activated protein kinase phosphorylation. Our results revealed that the anti-β2GP I /β2GP I complex was able to activate platelets, and this activation was inhibited by either the anti-GP I bα antibody or the apoER2' inhibitor. Results showed that the anti-β2GP I /β2GP I complex induced platelet activation via GP I bα and apoER2', which may then contribute to the prothrombotic tendency in APS patients.

关键词: anti-β2GP I /β2GP I complex     platelet     GP I bα     apoER2'     thrombosis    

Neutralizing monoclonal antibodies present new prospects to treat SARS-CoV-2 infections

Rongtao Lai, Tianhui Zhou, Xiaogang Xiang, Jie Lu, Haiguang Xin, Qing Xie

《医学前沿(英文)》 2021年 第15卷 第4期   页码 644-648 doi: 10.1007/s11684-021-0847-4

摘要: The coronavirus disease 2019 (COVID-19) has caused global public health and economic crises. Thus, new therapeutic strategies and effective vaccines are urgently needed to cope with this severe pandemic. The development of a broadly neutralizing antibody against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of the attractive treatment strategies for COVID-19. Currently, the receptor-binding domain (RBD) of the spike (S) protein is the main target of neutralizing antibodies when SARS-CoV-2 enters human cells through an interaction between the S protein and the angiotensin-converting enzyme 2 expressed on various human cells. A single monoclonal antibody (mAb) treatment is prone to selective pressure due to increased possibility of targeted epitope mutation, leading to viral escape. In addition, the antibody-dependent enhancement effect is a potential risk of enhancing the viral infection. These risks can be reduced using multiple mAbs that nonoverlapping epitopes. Thus, a cocktail therapy combining two or more antibodies that recognize different regions of the viral surface may be the most effective therapeutic strategy.

关键词: neutralizing antibody     antibody cocktail     SARS-CoV-2     COVID-19     therapeutic strategy    

Passive antibody therapy in emerging infectious diseases

《医学前沿(英文)》 2023年 第17卷 第6期   页码 1117-1134 doi: 10.1007/s11684-023-1021-y

摘要: The epidemic of corona virus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 and its variants of concern (VOCs) has been ongoing for over 3 years. Antibody therapies encompassing convalescent plasma, hyperimmunoglobulin, and neutralizing monoclonal antibodies (mAbs) applied in passive immunotherapy have yielded positive outcomes and played a crucial role in the early COVID-19 treatment. In this review, the development path, action mechanism, clinical research results, challenges, and safety profile associated with the use of COVID-19 convalescent plasma, hyperimmunoglobulin, and mAbs were summarized. In addition, the prospects of applying antibody therapy against VOCs was assessed, offering insights into the coping strategies for facing new infectious disease outbreaks.

关键词: SARS-CoV-2     COVID-19     convalescent plasma     hyperimmunoglobulin     neutralizing monoclonal antibodies    

A comprehensive analysis of immunoglobulin heavy chain genes in the Bactrian camel (

Zuoxiang LIANG,Tao WANG,Yi SUN,Wenlong YANG,Zhihong LIU,Jing FEI,Ying GUO,Qingwei MA,Qingjie PAN,Liming REN

《农业科学与工程前沿(英文)》 2015年 第2卷 第3期   页码 249-259 doi: 10.15302/J-FASE-2015056

摘要: Heavy chain only antibodies (HCAbs) represent a rare type of antibody that is devoid of light chains and the CH1 domain that have been reported in cartilaginous fish and camelids. By analyzing transcript data and genome sequences, we conducted a comprehensive analysis of Bactrian camel immunoglobulin heavy chain genes. Based on the transcript data, one gene, five genes, one gene and one gene were found. Additionally, the variable region of HCAbs (VHH) and the conventional antibodies (VH) sequences associated with the , and genes were amplified. Based on these genome sequences, seven , six , , , , , and genes and a portion of a gene were observed. Different Kozak sequences within different VH families were found in our analysis, and the variability index differed between the VHH3 and VH3 families. Phylogenetic analysis of the constant regions of the camelid immunoglobulin genes indicates that these genes appeared before the evolutionary divergence of Bactrian camels and dromedaries.

关键词: Bactrian camel     heavy-chain antibodies     VHH     γ3    

131I标记的人源化抗B7-H3抗体用于胶质母细胞瘤放射免疫疗法的治疗特性 Article

傅丰庆, Meng Zheng, Shandong Zhao, Yan Wang, Minzhou Huang, Hanqing Chen, Ziyi Huang, Kaijie Zhang, 缪丽燕, 张学光

《工程(英文)》 2023年 第30卷 第11期   页码 190-202 doi: 10.1016/j.eng.2023.05.011

摘要:

B7 homolog 3 (B7-H3) has attracted much attention in glioblastoma (GBM) radioimmunotherapy (RIT) due to its abnormally high expression on tumor cells. In this study, we report that two specific humanized anti-human B7-H3 antibodies (hu4G4 and hu4H12) derived from mouse anti-human B7-H3 antibodies that were generated by computer-aided design and exclusively recognize membrane expression of B7-H3 by human glioma cells. Hu4G4 and hu4H12 were radiolabeled with 89Zr for RIT antibody screening. Micro-positron emission tomography (PET) imaging, biodistribution and pharmacokinetic (PK) analyses of 89Zr-labeled antibodies were performed in U87-xenografted models. 125I labelling of the antibodies for single-photon emission computed tomography (SPECT) imaging was also used to investigate the biological behavior of the antibodies in vivo. Furthermore, the pharmacodynamic (PD) of the 131Ilabeled antibodies were evaluated in U87-xenografted mice and GL261 Red-FLuc-B7-H3 in situ glioma tumor models. Micro-PET imaging and biodistribution analysis with a gamma counter showed that 89Zr-deferoxamine (DFO)-hu4G4 had higher tumor targeting performance with lower liver uptake than 89Zr-DFO (hu4H12, immunoglobulin G (IgG)). The biodistribution results of 125I-SPECT imaging were similar to those of 89Zr-PET imaging, though the biodistribution in long bone joints and the thyroid varied. The PD analysis results indicated that 131I-hu4G4 had an excellent therapeutic effect and high safety with no apparent toxicity. Interestingly, 131I-hu4G4 improved the tumor vasculature in tissues with higher expression of collagen type IV and platelet-derived growth factor receptor b (PDGFR-b) compared with control treatment, as determined by immunofluorescence (IF), which contributed to inhibiting tumor growth. Taken together, our data indicate that hu4G4 exhibits good tumor targeting and specificity, achieves low nonspecific concentrations in normal tissues, and has acceptable PK characteristics. 131I-hu4G4 also exerts effective antitumor effects with an ideal safety profile. Therefore, we expect hu4G4 to be an excellent antibody for the development of GBM RIT.

关键词: B7-H3     Radioimmunotherapy     Glioblastoma     Pharmacokinetics     Pharmacodynamics    

标题 作者 时间 类型 操作

Emerging immunological strategies: recent advances and future directions

期刊论文

Preclinical characterization and comparison between CD3/CD19 bispecific and novel CD3/CD19/CD20 trispecificantibodies against B-cell acute lymphoblastic leukemia: targeted immunotherapy for acute lymphoblastic

期刊论文

Broadly neutralizing antibodies and vaccine design against HIV-1 infection

Qian Wang, Linqi Zhang

期刊论文

提升疗效的修饰型治疗性抗体国内外研究进展

戴济民, 张雪芹, 戴竞耀, 杨向民, 陈志南

期刊论文

Human monoclonal antibodies as candidate therapeutics against emerging viruses

null

期刊论文

Recent advances in “universal” influenza virus antibodies: the rise of a hidden trimeric interface in

Yulu Wang, Dan Hu, Yanling Wu, Tianlei Ying

期刊论文

Synthesis of haptens and production of antibodies to bisphenol A

Xiya ZHANG, Xiaoyun DONG, Sijun ZHAO, Yuebin KE, Kai WEN, Suxia ZHANG, Zhanhui WANG, Jianzhong SHEN

期刊论文

Durability of neutralizing antibodies and T-cell response post SARS-CoV-2 infection

Yun Tan, Feng Liu, Xiaoguang Xu, Yun Ling, Weijin Huang, Mingquan Guo, Ziyu Fu, Dongguo Liang, Miao Xu, Hongzhou Lu, Saijuan Chen

期刊论文

Characterization of polyclonal antibodies against nonstructural protein 9 from the porcine reproductive

Mengmeng ZHAO,Juanjuan QIAN,Jiexiong XIE,Tiantian CUI,Songling FENG,Guoqiang WANG,Ruining WANG,Guihong ZHANG

期刊论文

The biopharmaceutical industry in China: history and future perspectives

null

期刊论文

Anti-β glycoprotein I antibodies in complex with β2 glycoprotein I induce platelet activation via two

null

期刊论文

Neutralizing monoclonal antibodies present new prospects to treat SARS-CoV-2 infections

Rongtao Lai, Tianhui Zhou, Xiaogang Xiang, Jie Lu, Haiguang Xin, Qing Xie

期刊论文

Passive antibody therapy in emerging infectious diseases

期刊论文

A comprehensive analysis of immunoglobulin heavy chain genes in the Bactrian camel (

Zuoxiang LIANG,Tao WANG,Yi SUN,Wenlong YANG,Zhihong LIU,Jing FEI,Ying GUO,Qingwei MA,Qingjie PAN,Liming REN

期刊论文

131I标记的人源化抗B7-H3抗体用于胶质母细胞瘤放射免疫疗法的治疗特性

傅丰庆, Meng Zheng, Shandong Zhao, Yan Wang, Minzhou Huang, Hanqing Chen, Ziyi Huang, Kaijie Zhang, 缪丽燕, 张学光

期刊论文