As medicine progresses into a new era of personalised therapy, the use of monoclonal antibodies to treat a wide range of diseases lies at the heart of this new forefront. Since the licencing of the first monoclonal antibody for clinical use 30 years ago, the monoclonal antibody industry has expanded exponentially and is now valued at billions of dollars.
With major advances in genetic sequencing and biomedical research, much research into monoclonal antibodies now focuses on identifying new targets for development and maximising their efficacy for use in clinical practice. However, a balance has to be struck with regards to reducing numbers of side-effects and overall economic cost, which arguably somewhat blighted their early clinical and commercial successes.
Nowadays, there are approximately 30 monoclonal antibodies that have been approved for use in clinical practice with many more currently being tested in clinical trials. Some of the current major limitations include: the use of inefficient models for generation, a lack of efficacy and issues of cost-effectiveness. Some of the current research focuses on ways to improve the efficacy of existing monoclonal antibodies through optimising their effects and the addition of beneficial modifications.
This review will focus on the history of monoclonal antibody development – how it has increasingly moved away from using laborious animal models to a more effective phage display system, some of the major drawbacks from a clinical and economical point of view and future innovations that are currently being researched to maximise their effectiveness for future clinical use.
Keywords: Personalised medicine, Monoclonal antibodies, Therapeutic antibodies, Antibody development, Antibody modifications Go to: 1. Introduction
From the time the first monoclonal antibody was generated in 1975 and the first monoclonal antibody fully licenced in 1986, the field of monoclonal antibody development represents a novel way in which to target specific mutations and defects in protein structure and expression in a wide range of diseases and conditions. Today, with major rapid advancements in genetic sequencing and the translation of basic medical sciences research into clinical practice, humanised monoclonal antibodies are now the fastest growing group of biotechnology-derived molecules in clinical trials currently [1]. The global value of the antibody market is approximately $20 billion per year [2]. About 30 monoclonal antibodies are currently approved by the FDA for use in humans for treating various diseases and conditions including: cancer, chronic inflammatory diseases, transplantation, infectious diseases and cardiovascular diseases [3].
Go to: 2. Generation of monoclonal antibodies using the hybridoma technique
Monoclonal antibodies are monovalent antibodies which bind to the same epitope and are produced from a single B-lymphocyte clone [4]. They were first generated in mice in 1975 using a hybridoma technique [5]. The generation of hybridomas involves immunising a certain species against a specific epitope on an antigen and obtaining the B-lymphocytes from the spleen of the animal. The B-lymphocytes are then fused (by chemical- or virus-induced methods) with an immortal myeloma cell line lacking the hypoxanthine-guanine-phosphoribosyltransferase (HGPRT) gene and not containing any other immunoglobulin-producing cells. These hybridoma cells are then cultured in vitro in selective medium (i.e. medium containing hypoxanthine-aminopterin-thymidine) where only the hybridomas (i.e. the fusion between the primary B-lymphocytes and myeloma cells) survive as they have inherited immortality from the myeloma cells and selective-resistance from the primary B-lymphocytes (as the myeloma cells lack HGPRT, they cannot synthesise nucleotides de novo as this is inhibited by aminopterin in the selective medium) [4]. The initial culture of hybridomas contains a mixture of antibodies derived from many different primary B-lymphocyte clones, each secreting its own individual specific antibody into the culture medium (i.e. the antibodies are still polyclonal). Each individual clone can be separated by dilution into different culture wells. The cell culture medium can then be screened from many hundreds of different wells for the specific antibody activity required and the desired B-lymphocytes grown from the positive wells and then recloned and retested for activity [6]. The positive hybridomas and monoclonal antibodies generated can then be stored away in liquid nitrogen.
1. Introduction From the time the first monoclonal antibody was generated in 1975 and the first monoclonal antibody fully licenced in 1986, 【houtou72 注：这不是人源单抗】the field of monoclonal antibody development represents a novel way in which to target specific mutations and defects in protein structure and expression in a wide range of diseases and conditions. Today, with major rapid advancements in genetic sequencing and the translation of basic medical sciences research into clinical practice, humanised monoclonal antibodies are now the fastest growing group of biotechnology-derived molecules in clinical trials currently [1].
【1】Abstract Fully human monoclonal antibodies (mAbs) are a promising and rapidly growing category of targeted therapeutic agents. The first such agents were developed during the 1980s, 【houtou72注：我们的首例人源单抗正在文章所说的时间段内---虽然不知道该文作者是否曾知道我们当时研究的进展，但无疑，我们的研究在当时是属于世界领先的。】but none achieved clinical or commercial success. Advances in technology to generate the molecules for study — in particular, transgenic mice and yeast or phage display — renewed interest in the development of human mAbs during the 1990s. In 2002, adalimumab became the first human mAb to be approved by the US Food and Drug Administration (FDA). Since then, an additional six human mAbs have received FDA approval: panitumumab, golimumab, canakinumab, ustekinumab, ofatumumab and denosumab. In addition, 3 candidates (raxibacumab, belimumab and ipilimumab) are currently under review by the FDA, 7 are in Phase III studies and 81 are in either Phase I or II studies. Here, we analyse data on 147 human mAbs that have entered clinical study to highlight trends in their development and approval, which may help inform future studies of this class of therapeutic agents.....
Experiences in the production of human monoclonal antibodies
Comparative Study Dev Biol Stand . 1984;57:93-8. Experiences in the production of human monoclonal antibodies to tetanus toxoid J E Boyd, I Hastings, Z Farzad, K James, D B McClelland PMID: 6526155 Abstract
The production of human monoclonal antibodies has been attempted using tetanus toxoid as a model antigen since a human antibody of this specificity could have clinical applications. Both mouse and human myeloma cell lines were used as fusion partners and the effects of in vivo and in vitro antigen boosting were also investigated. A cell line, ES12, which secreted specific tetanus toxoid antibody arose following fusion of lymphocytes from a donor who had been boosted three months earlier. Antibody was secreted by this cell line at a high titre (2.5 I.U/ml); it was of IgG isotype and it protected mice against challenge with tetanus toxin. This is, therefore, a first step in producing a therapeutically useful monoclonal antibody.
最好不要低看了中国人。第一个人工合成具有生物活性的蛋白质分子。詹天佑火车车厢自动挂钩。钱学森弹道理论，青蒿素，于敏热核聚变理论。王淦昌对物理学的贡献。中国人的稀土元素的先进冶炼提纯方法。等等，等等等等。虽然比不上西方国家在科学上的贡献多，但绝不能说中国近200年中对科学的贡献为零。
另外，夸克学说不是美国人首先发明的，是中国人最先在青藏高原铺设的宇宙射线感应胶片获得的数据而提出的理论：层子理论，只是被后来美国科学舆论优先化了
美国的登月是冷战的假伪科技。是为了标榜美国的资本主义制度而为美国社会注射的兴奋剂。至今不能有任何一方面的技术重复再现。连整个计划的任何一张图纸都没有被发现有过的彻底的谎言。
我参与的世界第一个人（-鼠杂交瘤）单克隆抗体。开创了直接产生人类免疫球蛋白抗体技术的世界先河。
我参与的第一个单血样一次检验多种成分的实验方法。那是我刚毕业不久参加的同学们即兴的地下课题。一个不小心几个小年轻就世界领先了。
2002年当我合成病毒时就立刻发现了科研界用于合成病毒方法和理论的巨大危险漏洞。这个漏洞将导致病毒的自然泄露，也将一定会在公共传播时产生危险失控的病毒变异叠加效应。由此提出了病毒流行病学的病毒叠加变异学说。看看现在的病毒变异及其恶性大流行现实。
我在医学免疫学的贡献还有的之一（！）就是我的免疫学三定律。这是世界第一个在生物学和医学理论界建立的理论定律。解决了为什么许多药物必定会导致严重的临床副作用并造成并发症，导致肌体器官纤维化或肿瘤的科学理论依据。现在科学界专家还摸不着西药副作用原理的边际呢！这里不得不插句话说，现在医学界特别是医学临床对免疫学原理的应用知识远远达不到应有的知识水平。这些都是以现代最尖端的科学研究文章和最先进的科技成果所反映出来的不足而看到的。比如对mRNA疫苗的毒性途径，比如对病毒感染细胞受体的快速分析，等等这些临床医学研究急需的理论和技术，看看这些专家们，却还在知识外围上”鬼打墙“。
我在地质学和大气水文学方面的贡献是建立了沙漠温差内降水学说，破解了百多年人们对沙漠干旱的原因，破解了部分沙漠绿洲水源在无地下水和降水不足情况下有足够的水源来源之迷。为人类彻底征服沙漠解决了水源地问题。为今后人类自动地和大规模地从大气中获得洁净淡水提供了重要的理论和技术方向。这个在我十三四岁左右时就打下的理论雏形对未来人类社会生态环境的重要性无可估量。
我在天文学方面的理论就更多了：其中“每一个原生固体行星和卫星内部都必定有液态或固态的水存在”的行星定律仅仅是信手拈来。这个在我四岁就开始着迷并一直都没有放弃过思考的知识领域里，我自己都不知道我会总结出多少定律。
我在量子物理学的成果更也是自己都不知道能总结出多少理论：包括了量子纠缠依循泡利不相容原理规则。彩虹现象导出光速可变理论的提出.... ....
这还不包括我在技术应用方面的贡献呢。
犹太民族只有中国人口的几十分之一，但是对于现代社会做出的贡献比中国人多百倍
共五株。先给我自己注射三次破伤风毒素。然后采血收集淋巴细胞。在与小鼠的淋巴细胞瘤杂交筛选。
最后得到具有稳定的分泌人单克隆抗体的细胞株。两株IgG，三株IgM。
就是在这个过程中我提出了体外免疫绕过肿瘤患者体内的免疫抑制机能，在体外用癌细胞或抗原攻击离体血样来收集体外激活了的免疫细胞和免疫球蛋白抗体来回输到肿瘤患者体内来治疗癌症的想法。大约十多年后国际上才开始有人使用类似的方法用于不同的实验目的。
似乎我这辈子就是为科研而生的！
这个帖子时反驳那些认为近200年来中国人对世界科学贡献为零的观点而写的。原帖在时坛。被网管转移至此。一些包括我自己的跟帖全部丢掉了。在哪几个跟帖中，我还列出了一些自己在其它科学领域中的领先发现和发明。
否则主编不让发。
鄭氏車鉤[註 1][1]，是由美国人伊莱·H·詹尼（英语：Eli H. Janney）发明的自动车钩。
詹天佑在著作《新編華英工學字彙》中譯名為鄭氏車鉤，避開民間譯名詹氏車鉤，以避免被误解是詹天佑本人所发明的
与英语， 德语区人士无障碍交流， 神奇啵？
所谓“正确”的历史吧。
vs 200年后的
first monoclonal antibody fully licenced in 1986.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4284445/#:~:text=The%20first%20licenced%20monoclonal%20antibody,CD3%20expressed%20on%20T%2Dlymphocytes.
AbstractAs medicine progresses into a new era of personalised therapy, the use of monoclonal antibodies to treat a wide range of diseases lies at the heart of this new forefront. Since the licencing of the first monoclonal antibody for clinical use 30 years ago, the monoclonal antibody industry has expanded exponentially and is now valued at billions of dollars.
With major advances in genetic sequencing and biomedical research, much research into monoclonal antibodies now focuses on identifying new targets for development and maximising their efficacy for use in clinical practice. However, a balance has to be struck with regards to reducing numbers of side-effects and overall economic cost, which arguably somewhat blighted their early clinical and commercial successes.
Nowadays, there are approximately 30 monoclonal antibodies that have been approved for use in clinical practice with many more currently being tested in clinical trials. Some of the current major limitations include: the use of inefficient models for generation, a lack of efficacy and issues of cost-effectiveness. Some of the current research focuses on ways to improve the efficacy of existing monoclonal antibodies through optimising their effects and the addition of beneficial modifications.
This review will focus on the history of monoclonal antibody development – how it has increasingly moved away from using laborious animal models to a more effective phage display system, some of the major drawbacks from a clinical and economical point of view and future innovations that are currently being researched to maximise their effectiveness for future clinical use.
Keywords: Personalised medicine, Monoclonal antibodies, Therapeutic antibodies, Antibody development, Antibody modifications Go to: 1. IntroductionFrom the time the first monoclonal antibody was generated in 1975 and the first monoclonal antibody fully licenced in 1986, the field of monoclonal antibody development represents a novel way in which to target specific mutations and defects in protein structure and expression in a wide range of diseases and conditions. Today, with major rapid advancements in genetic sequencing and the translation of basic medical sciences research into clinical practice, humanised monoclonal antibodies are now the fastest growing group of biotechnology-derived molecules in clinical trials currently [1]. The global value of the antibody market is approximately $20 billion per year [2]. About 30 monoclonal antibodies are currently approved by the FDA for use in humans for treating various diseases and conditions including: cancer, chronic inflammatory diseases, transplantation, infectious diseases and cardiovascular diseases [3].
Go to: 2. Generation of monoclonal antibodies using the hybridoma techniqueMonoclonal antibodies are monovalent antibodies which bind to the same epitope and are produced from a single B-lymphocyte clone [4]. They were first generated in mice in 1975 using a hybridoma technique [5]. The generation of hybridomas involves immunising a certain species against a specific epitope on an antigen and obtaining the B-lymphocytes from the spleen of the animal. The B-lymphocytes are then fused (by chemical- or virus-induced methods) with an immortal myeloma cell line lacking the hypoxanthine-guanine-phosphoribosyltransferase (HGPRT) gene and not containing any other immunoglobulin-producing cells. These hybridoma cells are then cultured in vitro in selective medium (i.e. medium containing hypoxanthine-aminopterin-thymidine) where only the hybridomas (i.e. the fusion between the primary B-lymphocytes and myeloma cells) survive as they have inherited immortality from the myeloma cells and selective-resistance from the primary B-lymphocytes (as the myeloma cells lack HGPRT, they cannot synthesise nucleotides de novo as this is inhibited by aminopterin in the selective medium) [4]. The initial culture of hybridomas contains a mixture of antibodies derived from many different primary B-lymphocyte clones, each secreting its own individual specific antibody into the culture medium (i.e. the antibodies are still polyclonal). Each individual clone can be separated by dilution into different culture wells. The cell culture medium can then be screened from many hundreds of different wells for the specific antibody activity required and the desired B-lymphocytes grown from the positive wells and then recloned and retested for activity [6]. The positive hybridomas and monoclonal antibodies generated can then be stored away in liquid nitrogen.
1. Introduction
From the time the first monoclonal antibody was generated in 1975 and the first monoclonal antibody fully licenced in 1986, 【houtou72 注：这不是人源单抗】the field of monoclonal antibody development represents a novel way in which to target specific mutations and defects in protein structure and expression in a wide range of diseases and conditions. Today, with major rapid advancements in genetic sequencing and the translation of basic medical sciences research into clinical practice, humanised monoclonal antibodies are now the fastest growing group of biotechnology-derived molecules in clinical trials currently [1].
【1】Abstract
Fully human monoclonal antibodies (mAbs) are a promising and rapidly growing category of targeted therapeutic agents. The first such agents were developed during the 1980s, 【houtou72注：我们的首例人源单抗正在文章所说的时间段内---虽然不知道该文作者是否曾知道我们当时研究的进展，但无疑，我们的研究在当时是属于世界领先的。】but none achieved clinical or commercial success. Advances in technology to generate the molecules for study — in particular, transgenic mice and yeast or phage display — renewed interest in the development of human mAbs during the 1990s. In 2002, adalimumab became the first human mAb to be approved by the US Food and Drug Administration (FDA). Since then, an additional six human mAbs have received FDA approval: panitumumab, golimumab, canakinumab, ustekinumab, ofatumumab and denosumab. In addition, 3 candidates (raxibacumab, belimumab and ipilimumab) are currently under review by the FDA, 7 are in Phase III studies and 81 are in either Phase I or II studies. Here, we analyse data on 147 human mAbs that have entered clinical study to highlight trends in their development and approval, which may help inform future studies of this class of therapeutic agents.....
看看出土同时代的青铜车马，又有哪一个其他国家在那么早就有着那样高的精准铸造水平？
更还有三千多年前的司母戊大鼎。是世界第一重的祭祀用青铜烹具。即便在秦始皇时代也是千年多前的古代历史成就了。
最好别和中国人比历史。
2千年前，希腊艺术家就能准确把握，用雕塑细腻再现人物的心理活动。中国要到了《收租院》才达到相同水平，还是泥塑。
上面是行家的科普。
Comparative Study Dev Biol Stand . 1984;57:93-8. Experiences in the production of human monoclonal antibodies to tetanus toxoid J E Boyd, I Hastings, Z Farzad, K James, D B McClelland PMID: 6526155 Abstract
The production of human monoclonal antibodies has been attempted using tetanus toxoid as a model antigen since a human antibody of this specificity could have clinical applications. Both mouse and human myeloma cell lines were used as fusion partners and the effects of in vivo and in vitro antigen boosting were also investigated. A cell line, ES12, which secreted specific tetanus toxoid antibody arose following fusion of lymphocytes from a donor who had been boosted three months earlier. Antibody was secreted by this cell line at a high titre (2.5 I.U/ml); it was of IgG isotype and it protected mice against challenge with tetanus toxin. This is, therefore, a first step in producing a therapeutically useful monoclonal antibody.
西方的文化至今远没有进入到人类脱离动物本能的现代文明的水平。
老总孔子焚周典，虽然几乎焚断了华夏历史帝王的列宗传承。但其改教人性本源的“人之初，性本善”就已经标志着中华文化从动物的丛林社会意识进入到了人类道德文明历史了。而西方至今的文化仍然是丛林文化，从资本主义到帝国主义。其现代化的标志就是在道德文明大旗下的弱肉强食的丛林文化。这种文化再先进也带有追求动物原始的本性。所以列宁说过：“帝国主义是资本主义的对高阶段”， “帝国主义就是战争”。看看现在的社会，不言而喻。
所以，你谈及到西方文化时，不可否认于它们与中华文化在许多方面都有各自的特点。但中文化以对自然的”势“的眼界去观察自然。而西方的文化特征这方面绝不可于中华文化相比较。更不要说从文明的角度来考虑问题：来自孔子的思想文化意识早在两千五六百年前标志着华夏文明就开始脱离了原始动物的意识，进入了真正人类文明的阶段了。
再说一个例子：易学是距今三千五百多年以前的夏朝时，中国人就已经思考总结出来的事物和自然趋势变换的规律并预测未来。再有周易和宋易得到因天时天势变化而变的更进一步的完善。在西方的文化意识中大概仅有最肤浅的星座预测学意识，仅仅对人而言。更不要说肤浅到以至认为未来预测学时迷信的。
不要和中国人比历史。即便个别事情的个别例子各有特色，但总体上来说西方文化没有雄厚的底蕴和中华文明相比。他们是比不了的。