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Preclinical characterization and comparison between CD3/CD19 bispecific and novel CD3/CD19/CD20 trispecific

《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    

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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    

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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    

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BGB-A445, a novel non-ligand-blocking agonistic anti-OX40 antibody, exhibits superior immune activation

《医学前沿（英文）》 doi: 10.1007/s11684-023-0996-8

摘要： OX40 is a costimulatory receptor that is expressed primarily on activated CD4+, CD8+, and regulatory T cells. The ligation of OX40 to its sole ligand OX40L potentiates T cell expansion, differentiation, and activation and also promotes dendritic cells to mature to enhance their cytokine production. Therefore, the use of agonistic anti-OX40 antibodies for cancer immunotherapy has gained great interest. However, most of the agonistic anti-OX40 antibodies in the clinic are OX40L-competitive and show limited efficacy. Here, we discovered that BGB-A445, a non-ligand-competitive agonistic anti-OX40 antibody currently under clinical investigation, induced optimal T cell activation without impairing dendritic cell function. In addition, BGB-A445 dose-dependently and significantly depleted regulatory T cells in vitro and in vivo via antibody-dependent cellular cytotoxicity. In the MC38 syngeneic model established in humanized OX40 knock-in mice, BGB-A445 demonstrated robust and dose-dependent antitumor efficacy, whereas the ligand-competitive anti-OX40 antibody showed antitumor efficacy characterized by a hook effect. Furthermore, BGB-A445 demonstrated a strong combination antitumor effect with an anti-PD-1 antibody. Taken together, our findings show that BGB-A445, which does not block OX40–OX40L interaction in contrast to clinical-stage anti-OX40 antibodies, shows superior immune-stimulating effects and antitumor efficacy and thus warrants further clinical investigation.

关键词： BGB-A445     OX40     agonistic antibody     OX40L noncompetitive    

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Passive antibody therapy in emerging infectious diseases

《医学前沿（英文）》 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    

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Production of a polyclonal antibody to the VP26 nucleocapsid protein of white spot syndrome virus (wssv

Suchera LOYPRASERT-THANANIMIT, Akrapon SALEEDANG, Proespichaya KANATHARANA, Panote THAVARUNGKUL, Wilaiwan CHOTIGEAT

《化学科学与工程前沿（英文）》 2012年 第6卷 第2期   页码 216-223 doi: 10.1007/s11705-012-1289-y

摘要： White spot syndrome virus (WSSV) is a major cause of high mortality in cultured shrimp all over the world. VP26 is one of the structural proteins of WSSV that is assumed to assist in recognizing its host and assists the viral nucleocapsid to move toward the nucleus of the host cell. The objective of this work was to produce a polyclonal antibody against VP26 and use it as a biosensor. The recombinant VP26 protein (rVP26) was produced in (BL21), purified and used for immunizing rabbits to obtain a polyclonal antibody. Western blot analysis confirmed that the antiserum had a specific immunoreactivity to the VP26 of WSSV. This VP26 antiserum was immobilized onto a gold electrode for use as the sensing surface to detect WSSV under a flow injection system. The impedance change in the presence of VP26 was monitored in real time. The sensitivity of the biosensor was in the linear range of 160–160000 copies of WSSV, indicating that it is good and sensitive for analysis of WSSV. The specificity of the biosensor was supported by the observation that no impedance change was detected even at high concentrations when using Yellow Head Virus (YHV). This biosensor may be applied to monitor the amount of WSSV in water during shrimp cultivation.

关键词： recombinant protein     polyclonal antibody     label-free biosensor     impedance     white spot syndrome virus (WSSV)    

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Growth suppression of colorectal cancer expressing S492R EGFR by monoclonal antibody CH12

Qiongna Dong, Bizhi Shi, Min Zhou, Huiping Gao, Xiaoying Luo, Zonghai Li, Hua Jiang

《医学前沿（英文）》 2019年 第13卷 第1期   页码 83-93 doi: 10.1007/s11684-019-0682-z

摘要：

Colorectal cancer (CRC) is a common malignant tumor in the digestive tract, and 30%–85% of CRCs express epidermal growth factor receptors (EGFRs). Recently, treatments using cetuximab, also named C225, an anti-EGFR monoclonal antibody, for CRC have been demonstrated to cause an S492R mutation in EGFR. However, little is known about the biological function of S492R EGFR. Therefore, we attempted to elucidate its biological function in CRC cells and explore new treatment strategies for this mutant form. Our study indicated that EGFR and S492R EGFR accelerate the growth of CRC cells in vitro and in vivo and monoclonal antibody CH12, which specifically recognizes an EGFR tumor-specific epitope, can bind efficiently to S492R EGFR. Furthermore, mAb CH12 showed significantly stronger growth suppression activities and induced a more potent antibody-dependent cellular cytotoxicity effect on CRC cells bearing S492R EGFR than mAb C225. mAb CH12 obviously suppressed the growth of CRC xenografts with S492R EGFR mutations in vivo. Thus, mAb CH12 may be a promising therapeutic agent in treating patients with CRC bearing an S492R EGFR mutation.

关键词： S492R EGFR ectodomain mutation     colorectal cancer     mAb CH12     immunnotherapy    

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Preparation of hapten-specific monoclonal antibody for cadmium and its ELISA application to aqueous samples

Huan HE, Bo TANG, Cheng SUN, Shaogui YANG, Weijuan ZHENG, Zichun HUA

《环境科学与工程前沿（英文）》 2011年 第5卷 第3期   页码 409-416 doi: 10.1007/s11783-011-0349-8

摘要： High-affinity and specific monoclonal antibodies against cadmium-ethylene diamine tetraacetic acid (EDTA) complex have been produced using the hybridoma technique. A hapten was synthesized and characterized by Fourier Transform Infrared Spectroscopy (FT-IR) and UV-Vis. Competitive enzyme-linked immunosorbent assay (ELISA) for quantitative detection of cadmium in aqueous sample was developed. The monoclonal antibody with high level of binding affinity for Cd-IEDTA-BSA and high specificity for soluble Cd-EDTA complex showed less than 0.99% cross-reactivity with other 11 metals. The limit of detection was 0.10 μg·L , and the effective linear range was 10 –10 μg·L . The intra- and inter-assay coefficient variations were 1.5%–6.3% and 3.2%–7.4%, respectively. The spike recovery in different water samples were between 98.5% and 110.3%. The detection limit of this assay was well below the allowable concentration of cadmium (3 μg·L ), and the working range was wider than that of other methods which showed the range of 2.19–86.38 and 0–10 μg·L . The competitive ELISA established in this paper was sensitive and accurate in the screening of cadmium in aqueous samples. The results will lay a solid foundation for construction of an immunoassay kit for cadmium.

关键词： cadmium     hapten     monoclonal antibody     enzyme-linked immunosorbent assay (ELISA)    

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CD176 single-chain variable antibody fragment inhibits the adhesion of cancer cells to endothelial cells

null

《医学前沿（英文）》 2016年 第10卷 第2期   页码 204-211 doi: 10.1007/s11684-016-0443-1

摘要：

CD176 (Thomsen-Friedenreich antigen) is a tumor-associated carbohydrate epitope (glycotope) functionally involved in blood spread and liver metastasis of cancer cells by mediating the adhesion of cancer cells to endothelial cells and hepatocytes, respectively. CD176 could be a promising target for antitumor immunotherapy. We applied B lymphocytes obtained from mice immunized with CD176 antigen and constructed a phage display library. A positive clone of CD176 single-chain variable antibody fragment (scFv) was successfully screened from this library. The CD176 scFv was expressed in Escherichia coli and purified. The purified scFv can bind to the natural CD176 expressed on the surface of cancer cells. Furthermore, the CD176 scFv inhibits the adhesion of CD176+ cancer cells to endothelial cells and hepatocytes. This CD176 scFv provides a basis for future development of recombinant CD176-specific antibodies that can be used in therapeutic application.

关键词： CD176     Thomsen-Friedenreich antigen     scFv     cancer     therapy     adhesion     metastasis    

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使用数据驱动模型优化抗体纯化策略 Article

刘松崧, Lazaros G. Papageorgiou

《工程（英文）》 2019年 第5卷 第6期   页码 1077-1092 doi: 10.1016/j.eng.2019.10.011

摘要：

本工作致力于抗体片段纯化过程的多尺度优化。优化了生产过程中的色谱决策，包括色谱柱的数量及其大小，每批的循环数以及操作流速。使用基于微型实验数据的制造规模模拟数据集，建立了以负载质量、流速和柱床高度为输入的色谱通量数据驱动模型。与其他方法相比，分段线性回归建模方法具有简单、预测精度高的优点。提出了两种混合整数非线性规划（MINLP）模型，结合数据驱动模型，以最小化每克抗体纯化过程的总成本。然后，使用线性化技术和多参数分解将这些MINLP模型重新构造为混合整数线性规划（MILP）模型。研究了两个具有不同色谱柱尺寸替代品的工业相关案例，以证明所提出模型的适用性。

关键词： 抗体纯化     多尺度优化     抗原结合片段     混合整数规划     数据驱动模型     分段线性回归    

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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    

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一种通过计算机辅助抗体设计技术获得的靶向人表皮生长因子受体2的新型全人抗体HF Article

乔春霞, 吕明, 李新颖, 郞小玲, 吕守芹, 龙勉, 黎燕, 耿树生, 林周, 沈倍奋, 冯健男

《工程（英文）》 2021年 第7卷 第11期   页码 1566-1576 doi: 10.1016/j.eng.2020.10.024

摘要：

全人抗体免疫原性小、安全性高。目前研究的处于临床试验阶段的大多数抗体药物都是人源化或全人抗体。全人抗体多通过噬菌体展示技术（体外）或转基因小鼠（体内）产生；其他方法包括B淋巴细胞永生化、人-人杂交瘤、单细胞聚合酶链反应等。本文描述了一种基于分子结构的计算机辅助设计新抗体技术，用于获得全人抗体。由于靶向人表皮生长因子受体2（HER2）的注射用曲妥珠单抗（赫赛汀）的结构复杂，我们首先针对赫赛汀识别HER2 的潜在表位设计了6 条短肽。随后，将这些肽作为抗体互补决定区，并采用适合的免疫球蛋白框架，获得名为“HF”的新型抗HER2 抗体。HF比赫赛汀具有更高的亲和力和更有效的抗肿瘤活性。我们的工作为用于机理研究以及免疫相关疾病（如癌症和传染病）的成像和临床应用的新型全人抗体的快速设计和筛选提供了有用工具。

关键词： 人表皮生长因子受体2（HER2/erb-B2）     全人抗体     计算机辅助设计（CAD）    

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From SARS to MERS: evidence and speculation

null

《医学前沿（英文）》 2016年 第10卷 第4期   页码 377-382 doi: 10.1007/s11684-016-0466-7

摘要：

The Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel zoonotic pathogen. In 2012, the infectious outbreak caused by MERS-CoV in Saudi Arabia has spread to more than 1600 patients in 26 countries, resulting in over 600 deaths. Without a travel history, few clinical and radiological features can reliably differentiate MERS from SARS. But in real world, comparing with SARS, MERS presents more vaguely defined epidemiology, more severe symptoms, and higher case fatality rate. In this review, we summarize the recent findings in the field of MERS-CoV, especially its molecular virology, interspecies mechanisms, clinical features, antiviral therapies, and the further investigation into this disease. As a newly emerging virus, many questions are not fully answered, including the exact mode of transmission chain, geographical distribution, and animal origins. Furthermore, a new protocol needs to be launched to rapidly evaluate the effects of unproven antiviral drugs and vaccine to fasten the clinical application of new drugs.

关键词： middle east respiratory syndrome     animal origin     cross-species transmission     monoclonal antibody    

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Reduction of rough set attribute based on immune clone selection

LIANG Lin, XU Guang-hua

《机械工程前沿（英文）》 2006年 第1卷 第4期   页码 413-417 doi: 10.1007/s11465-006-0049-4

摘要： A novel attribute reduction approach of rough set based on immune clone selection is proposed. In this method, the approximation quality and attribute set were adopted as evolution object and antibody, respectively. On the basis of the inherent distribution within the immune response, the global optimization of the antibody was realized through parallel local optimization. Moreover, the diversity of the antibody population was maintained with the affinity maturation and renewal of the antibody. Thus, the stable multi-optimal solutions can be preserved. In addition, the machinery fault data were analyzed by this method, and the attribute reduction sets were obtained further to satisfy the demand of feature selection in machinery diagnosis.

关键词： inherent distribution     maturation     evolution     diversity     antibody    

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靶向膜蛋白的抗体药物开发的新进展 Review

Georgina To’a Salazar, 黄子逸, 张凝艳, 张学光, 安志强

《工程（英文）》 2021年 第7卷 第11期   页码 1541-1551 doi: 10.1016/j.eng.2020.11.013

摘要：

在疾病干预的众多膜蛋白靶标中，G蛋白偶联受体（GPCR）作为人体内最大的膜受体蛋白家族，成为很多药物的重要靶点，其次是离子通道、转运蛋白和激酶等。膜蛋白在细胞信号转导和运输中发挥了关键作用，当前药物研发面临的挑战在于进一步发掘此类膜蛋白的潜在靶点的干预价值，开发治疗性抗体药物。鉴于特异性抗体能够识别膜蛋白的灵敏特性，以及随着基因工程技术的进步，对已有抗体进行加工改造可获得适应多个靶点蛋白的特异性抗体。然而，成功分离特异靶向膜蛋白抗体取决于一系列因素。我们更易研制和识别结构简单且具有长片段胞外区的抗体分子，但对于高难度的靶点蛋白，如GPCR和其他复杂膜蛋白往往难以得到具有活性的候选抗体。目前若要开发针对复杂膜蛋白（如GPCR、离子通道、转运蛋白和激酶）的抗体药物，必须从抗原靶点设计、抗体筛选策略、先导抗体优化及药物研发模式方面进行考虑。深入研究靶标膜蛋白的结构有助于推进治疗性抗体药物的开发进程。本文概述了抗体靶向复杂膜蛋白的优势和挑战，以及膜蛋白抗原制备和抗体研发策略的最新进展。

关键词： 抗体治疗     复杂膜蛋白     离子通道     转运蛋白     膜结合酶     G蛋白偶联受体     药物发现    

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标题 作者 时间 类型 操作

Preclinical characterization and comparison between CD3/CD19 bispecific and novel CD3/CD19/CD20 trispecific

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

Emerging immunological strategies: recent advances and future directions

期刊论文

BGB-A445, a novel non-ligand-blocking agonistic anti-OX40 antibody, exhibits superior immune activation

期刊论文

Passive antibody therapy in emerging infectious diseases

期刊论文

Production of a polyclonal antibody to the VP26 nucleocapsid protein of white spot syndrome virus (wssv

Suchera LOYPRASERT-THANANIMIT, Akrapon SALEEDANG, Proespichaya KANATHARANA, Panote THAVARUNGKUL, Wilaiwan CHOTIGEAT

期刊论文

Growth suppression of colorectal cancer expressing S492R EGFR by monoclonal antibody CH12

Qiongna Dong, Bizhi Shi, Min Zhou, Huiping Gao, Xiaoying Luo, Zonghai Li, Hua Jiang

期刊论文

Preparation of hapten-specific monoclonal antibody for cadmium and its ELISA application to aqueous samples

Huan HE, Bo TANG, Cheng SUN, Shaogui YANG, Weijuan ZHENG, Zichun HUA

期刊论文

CD176 single-chain variable antibody fragment inhibits the adhesion of cancer cells to endothelial cells

null

期刊论文

使用数据驱动模型优化抗体纯化策略

刘松崧, Lazaros G. Papageorgiou

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

一种通过计算机辅助抗体设计技术获得的靶向人表皮生长因子受体2的新型全人抗体HF

乔春霞, 吕明, 李新颖, 郞小玲, 吕守芹, 龙勉, 黎燕, 耿树生, 林周, 沈倍奋, 冯健男

期刊论文

From SARS to MERS: evidence and speculation

null

期刊论文

Reduction of rough set attribute based on immune clone selection

LIANG Lin, XU Guang-hua

期刊论文

靶向膜蛋白的抗体药物开发的新进展

Georgina To’a Salazar, 黄子逸, 张凝艳, 张学光, 安志强

期刊论文