我国抗体药物产业化发展的策略探讨

随着重组抗体药物展示出良好的治疗效果和市场效益,抗体药物的研发逐渐成为生物医药产业发展的主要方向。但是目前国内动物细胞表达水平普遍较低和发酵工艺落后的现状制约了我国抗体药物产业化的发展。主要综述了国际抗体药物产业的发展态势,重点比较二氢叶酸还原酶和谷氨酰胺合成酶表达体系、连续灌注和流加培养发酵模式的各自优势,结合我们抗体药物表达、发酵方面的经验,对当前我国抗体药物产业化发展策略进行了探讨,提出抗体药物产业化模式应根据企业对抗体产率、产能和市场经济学的多重考虑选择发酵工艺和发酵规模,应用谷氨酰胺合成酶/CHO-K1表达系统和连续灌注培养工艺可能更适应目前中国抗体产业化的需要。     

重组抗体药物的研究进展

重组抗体药物发展历程为:鼠源单克隆抗体——人—鼠嵌合抗体——人源化抗体——全人抗体。抗体药物基因工程改造遵循了降低抗体的免疫原性以及保持和提高抗体的亲和力这两个原则。本文就当前重组抗体药物的主要问题、基本情况以及解决办法加以阐述。     

重组抗体药物研究进展及应用

重组抗体药物的发展经历了鼠源单克隆抗体（McAb）、人 鼠嵌合抗体、人源化抗体和全人抗体等阶段,目前初步应用于抗肿瘤、抗自身免疫病、抗感染等领域。保持和提高抗体的亲和力、降低抗体的免疫原性是抗体药物基因工程改造的两大原则。在嵌合抗体成功的基础上,通过CDR移植、表面修饰、抗体库以及转基因鼠技术,逐步提高人源化程度至100%。然而,实验室水平的研究结果与实际应用仍然存在一定差距。就重组抗体药物的基本概况、现存的问题与可能的解决办法以及在肿瘤、病毒性疾病和阿尔茨海默病治疗上的应用情况等进行了综述。     

聚焦抗体药物产业发展

<正>抗体药物具备特异性高、性质均一、有效性和安全性等优点,在各种疾病治疗、特别是对肿瘤治疗的应用前景备受关注。当前,抗体药物的研发已成为生物制药领域最受瞩目的发展方向和研究热点,是"重磅炸弹"药物相对集中的领域之一。同时,抗体药物也是医药行业中高技术含量、高附加值、高门槛的产品类群。     

抗体药物的发展与应用

早期抗体药物是鼠源单克隆抗体,存在免疫原性强、半衰期短等问题。历经数十年的发展,抗体药物从最初的鼠源单抗,逐步发展为人鼠嵌合抗体、人源化抗体及全人源化抗体。通过片段重组、位点修饰、药物偶联等方法,科研人员研发了包括抗体融合蛋白、抗体偶联药物、双特异性抗体、小分子抗体片段等形式多样的抗体药物。抗体药物在恶性肿瘤、自身免疫病、感染性疾病的治疗上发挥重要作用。通过对抗体药物人源化历程,不同类型的抗体结构和特点,以及抗体药物在新型冠状病毒肺炎治疗中的应用进行综述,并对抗体药物的发展前景进行展望,以期为我国抗体药物的研发提供参考。     

治疗性抗体药物差异化研发策略

治疗性抗体药物在临床上取得了巨大的成功,然而在有效性和安全性方面还有待提高,同时药物靶点过于集中造成了重复开发、资源浪费等问题。因此,医药企业在研发抗体药物时需要探寻差异化的研发策略,从而在激烈的市场竞争中生存和发展。文中从药物的来源、结构形式、靶点选择、药物作用机制和差异化药物特性等方面探讨了治疗性抗体药物的差异化研发策略。     

长效重组蛋白药物发展动态

部分重组蛋白药物存在半衰期短的缺陷,临床给药频率高,且大多为注射给药,严重影响患者使用依从性。长效重组蛋白药物是近年来生物技术药物发展的重要趋势之一。对蛋白分子进行改造或修饰,延长重组蛋白药物的半衰期,实现长效以减少给药频率主要通过4种方式:化学修饰、构建突变体、蛋白融合、糖基化修饰。针对上述4种长效化方式及已上市相关产品进行了综述。展望未来,紧跟国外先进技术和质量标准发展,进一步提高国产长效重组蛋白药物质量水平,推进国内相关产品标准升级,推动创新长效重组蛋白药物开发及专利布局是未来几年国内该领域的发展方向。     

抗体药物开启生物医药发展新时代

<正>治疗性抗体药物在生物医药中的研究发展是最快的。自1986年美国FDA批准第一个治疗性抗体上市以来,抗体药物的研发得到快速发展。迄今已有35个抗体药物批准上市,目前处在临床研究的抗体药物350多个,处在Ⅲ期临床研究的抗体药物约有30个,用于癌症、炎症或免疫疾病、高胆固醇、骨质     

中国抗体药物产业现状与发展前景

我国抗体药物起步晚,研发与生产技术与国际水平相比尚有一定的差距,但我国抗体药物产业发展迅速,国家政策支持以及研发投入力度较大,目前已取得一定的成果,市场潜力巨大。根据近年来国内相关文献报道以及CFDA、CDE网站的数据库,对我国抗体药物的上市、注册、审批情况以及产业化现状、重点研发企业、发展方向等方面进行归纳总结。综述了我国抗体药物的研究进展及发展前景,为生物制药企业及从事生产研发的科研人员提供了参考依据。     

抗体药物研发现状与发展态势

抗体药物是以细胞工程技术和基因工程技术为主体的抗体工程技术制备的药物,具有特异性高、性质均一、可针对特定靶点定向制备等优点,在各种疾病治疗,特别是肿瘤治疗领域的应用前景备受关注。当前,抗体药物的研究与开发已成为生物技术药物领域研究的热点,居近年来所有医药生物技术产品之首。从分子构成来看．抗体药物可分为三类：①抗体或抗体片段．完整的抗体包括嵌合抗体、人源化抗体、人源抗体：抗体片段包括Fab等;     

国外动物生物技术研究和产业化趋势分析

生物技术在全世界范围取得了飞速的进展,与此同时其应用和产业化在各国政府、科研机构和生物技术公司的大力参与和激烈竞争中也逐步加快,预计它将成为许多国家经济的重要支柱产业之一。一些重大生物研究项目如人类基因组计划、克隆技术等开始引起公众的广泛注意。综述了２０世纪９０ 来动物生物技术的发展状况,对基因组研究、转基因动物、克隆技术和细胞培养等重要研究方向作了介绍和分析。     

Strategy for analysis and screening of bioactive compounds in traditional Chinese medicines

Traditional Chinese medicines (TCMs), due to their long time clinic test and reliable therapeutic efficacy, are attracting increased global attention served as excellent pools of bioactive compounds for the discovery of new drugs. However, hundreds or even thousands of components are usually contained in traditional Chinese medicines and only a few compounds are responsible for the pharmaceutical and/or toxic effects. The large numbers of other components in traditional Chinese medicines make the screening and analysis of the bioactive components extremely difficult. By the way, the combination effect of bioactive components on the pharmacological activity makes it very difficult to clear the therapeutic mechanism of TCMs. Therefore, some strategies have to design for screening of bioactive compounds in traditional Chinese medicines, which further leads to disclose the therapeutic mechanism of TCMs in molecular level. The review will summarize the present state of the art of screening strategy for active compounds in traditional Chinese medicines, and the chromatography methods for screening and analysis of bioactive compounds in traditional Chinese medicines will be emphasized.     

Strategy for obtaining non-native protein structures using antibody cross-reactions

Antibodies made to short peptides or to unfolded forms of proteins are often found to cross-react with intact proteins. These cross-reactions can be used to populate non-native protein conformations, possibly including protein folding intermediates, and the structures of the non-native conformations can be characterized using amide proton exchange and two-dimensional NMR.     

三倍体毛白杨组培快繁和工厂化育苗技术研究

采用1年生三倍体毛白杨优质苗木单芽茎段,研究其组织培养技术和工厂化育苗技术。研究结果表明,组培苗增殖与生根同步进行,通用最佳培养基为：H NAA0．15mg/L,生根率80％～98％,年增殖次数8次,繁殖系数为5。蛭石粉 泥炭土(1：1)是三倍体毛白杨组培苗炼苗的最佳基质。通过组培苗生产、温棚炼苗和大田炼苗试验,研究出了包括接种培养阶段、移栽和苗圃管理阶段3个连续过程的三倍体毛白杨工厂化育苗的工艺流程。     

High-throughput analysis of concentration-dependent antibody self-association

Monoclonal antibodies are typically monomeric and nonviscous at low concentrations, yet they display highly variable associative and viscous behavior at elevated concentrations. Although measurements of antibody self-association are critical for understanding this complex behavior, traditional biophysical methods are not capable of characterizing such concentration-dependent self-association in a high-throughput manner. Here we describe a nanoparticle-based method, termed self-interaction nanoparticle spectroscopy, that is capable of rapidly measuring concentration-dependent self-interactions for three human monoclonal antibodies with unique solution behaviors. We demonstrate that gold nanoparticles conjugated with antibodies at low protein concentrations (<40 μg/mL) display self-association behavior (as measured by the interparticle distance-dependent plasmon wavelength) that is well correlated with static light-scattering measurements obtained at three orders of magnitude higher antibody concentrations. Using this methodology, we find that the antibodies display a complex pH-dependent self-association behavior that is strongly influenced by the solution ionic strength. Importantly, we find that a polyclonal human antibody is nonassociative for all solution conditions evaluated in this work, suggesting that antibody self-association is more specific than previously realized. We expect that our findings will guide rational manipulation of antibody phase behavior, and enable studies that elucidate sequence and structural determinants of antibody self-association.     

Idiotypic analysis of a monoclonal anti-Sm antibody

Among murine models of autoimmunity, MRL mice are unique in their expression of antibodies to the nuclear antigen Sm. To assess genetic mechanisms in the control of this response, the idiotypes borne by a monoclonal anti-Sm antibody of MRL-Ipr/Ipr origin were investigated. Rabbit antisera were prepared against Y2, a hybridoma product with anti-Sm activity, and were rendered specific for idiotype by extensive absorption with normal globulins from BALB/c mice. In assays of idiotype by an inhibition ELISA, Y2 was shown to share idiotypes with Y12, another monoclonal anti-Sm derived from the same fusion as Y2; other monoclonal autoantibodies of MRL origin but different antigenic specificity failed to display idiotype activity in this assay. The presence of other anti-idiotypic specificities was revealed by absorption and elution of the anti-idiotype from an MRL globulin column; sera from both anti-Sm-positive and negative mice demonstrated these idiotypes. These results suggest that the predominant specificities detected by the anti-idiotype were unique to the monoclonal antibodies of the same animal, although there was also activity to idiotypes not related to anti-Sm binding molecules.     

一种特异性识别斑马鱼卵黄蛋白原的噬菌体展示单链抗体的可溶性表达方案

为了实现特异性识别斑马鱼卵黄蛋白原的噬菌体展示单链抗体的可溶性表达,将不能以可溶性蛋白形式表达的、只能以噬菌体展示形式特异性识别斑马鱼卵黄蛋白原的单链抗体F5的基因,克隆到pET 32a载体并转化入大肠杆菌ori DE3中。结果表明,通过诱导表达,可获得可溶性的并且仍特异性识别斑马鱼卵黄蛋白原的单链抗体32a-F5。噬菌体展示单链抗体不能可溶性表达是噬菌体展示技术应用中常见的问题,该方法提供了一种表达可溶性单链抗体的可行性方案。     

蝴蝶饲养与产业的发展

蝴蝶资源的可持续性利用,可以通过人工饲养的途径来实现.人工饲养分全虫态饲养和非全虫态饲养.依据蝴蝶的生物学特性,满足饲养蝶种对生态环境的要求,是人工饲养获得成功的关键.蝴蝶的成功饲养、产业的持续发展和开拓创新,都离不开高素质人材.因此,应把人力资源建设放在蝴蝶饲养与产业发展的第一位.生态蝴蝶园建设,则列为蝴蝶资源多种利用的首选项目.     

Monoclonal antibody analysis of Perkinsus marinus extracellular products

The protozoan oyster parasite Perkinsus marinus releases a complex set of extracellular products (ECP) during in vitro culture. These products have been previously implicated in parasite virulence, and their expression can be altered by medium supplementation with oyster tissue homogenate. Little is known regarding ECP function, regulation, or mechanism of storage and release. Perkinsus marinus ECP were purified from a protein-free medium and used to produce a panel of five monoclonal antibodies. Several of the antibodies recognised series of proteins implying that the ECP may originate from comparatively few parental molecules. The ECP are secreted by several pathways, including the release of one product from an external cell layer, and two other products from two morphologically distinct intracellular compartments. Antibodies against separate epitopes on one protein provided information about possible protein structure. A sandwich ELISA format allowed sensitive quantification of that protein and showed significantly reduced protein expression in oyster tissue homogenate supplemented cultures. Immunopurification allowed tandem mass spectroscopic amino acid sequencing of that protein. Another antibody was used to characterise the P. marinus cell wall. This antibody specifically bound to trophozoite and tomont walls, and was used to investigate the morphological and antigenic changes in these walls during Ray's fluid thioglycollate medium-induced formation of hypnospores. It was also used to confirm that oyster tissue homogenate supplementation could induce formation of hypnospores. This antibody labeled P. marinus cells in fixed oyster tissue in a species-specific manner.