治疗性单克隆抗体药物的现状及发展趋势

治疗性单克隆抗体药物经历了三十多年的发展,已经成为生物医药的最重要组成部分之一.在疾病治疗上具有广阔的应用前景,成功用于治疗肿瘤、自身免疫性疾病、感染性疾病和移植排斥反应等多种疾病.截至2012年已有29种治疗性单克隆抗体药物通过FDA审批并上市销售.治疗性单抗的安全性和有效性很大程度上由其作用的靶点决定,上市和在研的单抗药物有些靶向相同的靶点,有些有自己独特的作用靶点,新的作用靶点也在不断出现.以治疗性单抗的作用靶点为切入点,对目前上市销售和研发中的此类药物进行了简要总结.详述了肿瘤坏死因子α、白细胞分化抗原20、表皮生长因子受体及血管内皮生长因子等4种靶点的特点及相关单克隆抗体药物的情况,并对我国单抗药物的现状进行了分析,提出未来发展对策.     

抗体药物现状及发展趋势

治疗性抗体作为一种具有独特优势的生物靶向治疗药物,已成为目前全球药物研发的热点。截止到2013年2月,已有34个治疗性抗体获得美国FDA批准上市,用于各种疾病的治疗。据统计,目前有多达350余种抗体产品正处于临床试验阶段,其中29个已进入III期临床试验。开发抗体新靶点和新适应证,研究和设计更为安全有效的新型抗体分子及抗体组合疗法,寻找生物标记指导抗体对病人的有效治疗,是当前和今后一段时期内该领域发展的主要方向。本文将综述国际抗体药物研发现状和发展趋势,并对国内抗体药物现状及发展策略予以简要陈述。     

抗体生产纯化技术进展

自1997年FDA批准第一个治疗淋巴癌的嵌合单抗药物Rituxan,Anti-CD-20抗体上市,并进入56个国家,至2007年,FDA已批准了20多种治疗性单抗药物,约一半用于治疗癌症（详见附录1）,多个已成为年销售额超十亿美元的“炸弹药物”（Blockbuster Drug,图1）。全球抗体药物的市场增长十分迅猛,有约200多种单抗在临床实验,占整个临床生物技术药品总数的三分之一多,     

全球微生态药物研发现状及发展趋势 *

微生态药物在许多复杂性和慢性疾病中显示出极大的潜力,逐渐成为国际制药行业的新趋势。基于科睿唯安旗下的Cortellis数据库,采用定量分析和专家智慧相结合的方法,从总体研发现状、主要国家/地区、主要适应症、重点企业研发管线、重点在研药物、商业化交易多个维度展现全球微生态药物的研发和商业化全景。分析结果显示:全球共有142个在研微生态药物,其中49个药物处于临床阶段。美国在微生态药物研发和商业化方面遥遥领先,其数量占在研药物总量的70%。在研药物的适应症主要集中于炎症性肠病、艰难梭菌感染、溃疡性结肠炎等肠道感染性疾病。4D pharma公司的在研药物数量最多,微生态药物重点研发企业均建立起核心技术平台。处于临床3期的微生态药物共有7个,全球微生态药物商业化交易共有303起,最大的交易金额是27.8亿美元。未来,微生态药物有望在更难被人类征服的肿瘤和神经系统疾病方面取得突破性进展。     

全球微生态药物研发现状及发展趋势

微生态药物在许多复杂性和慢性疾病中显示出极大的潜力,逐渐成为国际制药行业的新趋势。基于科睿唯安旗下的Cortellis数据库,采用定量分析和专家智慧相结合的方法,从总体研发现状、主要国家/地区、主要适应症、重点企业研发管线、重点在研药物、商业化交易多个维度展现全球微生态药物的研发和商业化全景。分析结果显示:全球共有142个在研微生态药物,其中49个药物处于临床阶段。美国在微生态药物研发和商业化方面遥遥领先,其数量占在研药物总量的70%。在研药物的适应症主要集中于炎症性肠病、艰难梭菌感染、溃疡性结肠炎等肠道感染性疾病。4D pharma公司的在研药物数量最多,微生态药物重点研发企业均建立起核心技术平台。处于临床3期的微生态药物共有7个,全球微生态药物商业化交易共有303起,最大的交易金额是27. 8亿美元。未来,微生态药物有望在更难被人类征服的肿瘤和神经系统疾病方面取得突破性进展。     

抗体偶联药物的研究进展与质量控制

抗体偶联药物（antibody-drug conjugates,ADC）因其良好的靶向性及抗癌活性目前已成为抗肿瘤抗体药物研发的新热点和重要趋势,受到越来越多的关注。ADC药物由单克隆抗体、高效应的细胞毒性物质以及连接臂三部分组成,它将抗体的靶向性与细胞毒性药物的抗肿瘤作用相结合,可以降低细胞毒性抗肿瘤药物的不良反应,提高肿瘤治疗的选择性,还能更好地应对靶向单抗的耐药性问题。与传统单抗药物相比,因其结构复杂,ADC药物质量属性分析方法的建立具有更大的难度和特殊性。对抗体偶联药物的研发现状、质量属性分析方法和挑战以及质量控制要点进行了简要介绍,为ADC药物的研究和质量控制提供参考。     

治疗性抗体的市场考量和靶点分析

<正>近年来,单抗药物因其独特的分子靶向性和良好的临床疗效成为全球研发的热点,治疗性抗体成为产业界及学术界合作研发的令人振奋的领域。目前,在美国和欧盟有约33种市场在售和约30种处于临床Ⅲ期的治疗性抗体药物,主要用于肿瘤、炎症和自身免疫病及其他一些疾病的治疗。主要对近几年单抗药物的市场状况及治疗靶点进行了概述。     

全球双特异性抗体药物研发格局分析*

过去十年,全球双特异性抗体研发取得了突破性进展,4款产品获批上市,多个产品进入临床及临床前研究。双抗具有区别于单抗的独特生物学机制,有望成为针对癌症、自身免疫和传染病的下一代生物疗法,但双抗药物的开发更具复杂性,有着更高的技术壁垒。通过对全球双抗总体研发进展、企业研发格局、产品研发进展等角度分析,以期为相关企业的双抗研发方向选择及地区产业决策提供参考。     

针对CD33分子的抗体偶联药物的研究进展

单克隆抗体因具有分子量小、毒副作用低、靶向性好等优点,近年来已成为肿瘤治疗用药的主要方式。CD33分子是免疫球蛋白超家族成员,同时也是唾液酸依赖的免疫球蛋白样凝集素家族的成员,在免疫调节过程中具有重要作用。CD33分子特异表达于白血病细胞表面而在造血干细胞中不表达,因而成为白血病免疫治疗的理想靶点。以CD33为靶点的抗体药物主要有CMA676、HUMl95、AVE9633、WM537LHIM3-4等,目前大多处于临床试验阶段。该实验室也在进行抗CD33全人源抗体的研究,利用噬菌体展示技术筛选与CD33胞外区特异性结合的单链抗体,并构建免疫毒素和抗体偶联药物以研究其体内外抗肿瘤作用。该文针对CD33分子及其抗体偶联药物的现状及趋势作一综述。     

全球PD-1/PD-L1单克隆抗体市场竞争格局

目的:从产品开发角度分析PD-1/PD-L1单克隆抗体的发展现状和未来趋势。方法:检索科睿唯安(Clarivate Analytics)的Cortellis数据库的数据,利用定量分析法和对比分析法对检索结果进行分析。结果:目前已有5种PD-1/PD-L1单克隆抗体上市、4种PD-1/PD-L1单克隆抗体处于预注册及6种PD-1/PD-L1单克隆抗体处于临床Ⅲ期,未来市场上的PD-1/PD-L1单克隆抗体将呈现快速增长趋势。此外,PD-1/PD-L1单克隆抗体的商业交易也越来越多,目前共发生包括药物开发及商业化许可、专利资产出售及早期药物研发合作等10余起交易,其中药物开发及商业化许可是最主要的交易模式。结论:虽然PD-1/PD-L1单克隆抗体市场尚处于起步阶段,但随着未来技术的不断发展改进,相信未来有更多的PD-1/PD-L1单克隆抗体上市,为癌症及其他疾病的治疗提供新的契机。     

六种藓类植物茎的比较解剖学研究

通过对6种藓类植物,即褶叶青藓(Brachythecium salebrosum(Web.et Mohr.)B.S.G.)、湿地匐灯藓(Plagiomnium acutum(Lindb.)Kop.)、侧枝匐灯藓(Plagiomnium maximoviczii(Lindb.)Kop.)、大凤尾藓(Fissidensnobilis Griff.)、大羽藓(Thuidium cymbifolium(Doz.et Molk.)B.S.G.)和大灰藓(Hypnum plumaeforme Wils.)嫩茎和老茎的石蜡切片和显微观察发现,同一藓类植株的嫩茎和老茎,茎结构稳定,不同种藓类植物茎横切面具有不同特征.植物体茎横切面形状、表层细胞的层数、细胞大小和细胞壁厚薄、皮层细胞大小和形状、中轴的有无以及比例等特征可以作为藓类植物的分科分类依据之一.     

Cause of Senescence of Nine Sorts of Flowers

The levels of endogenous phytohormones and respiratory rate in nine sorts of flowers such as Cymbidium faberi Rolfe, Nopalxochia ackermannii Kunth and others were investigated both at full bloom and senescence and meanwhile the effect of exogenous phytohormones on prolonging the blossoms and promoting ethylene production were tested. There is a high content of endogenous ethylene in all the long-lived flowere, about 3–16 folds higer than the short-lived ones. There is a high level of ABA at full blooming flowers of short-lived flowers, in which there is no or only some cytokinins in it, but the ratio of CTK (6BA+zeatin)/ABA is smaller(l.7). The endogenous ABA reached a much higher level at senescence in all nine sorts of flowers, so it is reasonable to consider that it is ABA which plays an important role of regulation in controlling flower's senescence. There is a much higher level of GA3 and zeatin in the long-lived flowers which is not demonstrated in the shortlived ones. The respiratory rate is one of the factors controtling the longevity of flowers, but it does not play a decided role. Application of 6BA and zeatin prolongs distinctly orchid’s longevity, however exogenous IAA through the promotive action on ethylene production, evidently extends the longevity of the flowers of the Nopalxochia ackermannii Kunth.     

Photoregulation of seed germination of wild-type and of an aurea-mutant of tomato

Seed germination of an aurea mutant of tomato ( Lycopersicon esculentum Mill.) is promoted by continuous irradiation with red, far-red or long-wavelength far-red (758 nm) light as well as by cyclic irradiations (5 min red or 5 min far-red/25 min darkness). Far-red light applied immediately after each red does not change the germination behaviour. Seed germination of the isogenic wild-type, cv. UC-105, is promoted by continuous and cyclic red light while it is inhibited by continuous and cyclic far-red light and by continious 758 nm irradiation. Far-red irradiation reverses almost completely the promoting effect of red light. The promoting effect (in the aurea mutant) and the inhibitory effect (in the wild-type) of continuous far-red light do not show photon fluence rate dependency above 20 nmol m⁻² s⁻¹. It is concluded that phytochrome controls tomato seed germination throgh low energy responses in both the wild type and the au mutant. The promoting effect of continuous and cyclic far-red light in the au mutant can be attributed to a greater sensitivity to P_fr.     

龙胆科药用植物化学成分的研究现状

龙胆科植物在我国的分布范围很广,且多数为药用植物,其多数种属的药用植物,至今其化学成分尚未被系统研究。综述了目前龙胆科药用植物的化学成分的研究现状及一般提取方法,对近年来发现的环烯醚萜及裂环烯醚萜类化合物进行了总结,为本科药用植物的更深入研究提供了参考。     

The effects of glutamine of the maintenance of embryogenic cultures of Cryptomeria japonica

Summary Embryogenic tissues of sugi (Cryptomeria japonica) were induced on a modified Campbell and Durzan (CD) medium containing 1 μM 2,4-dichlorophenoxyacetic acid (2,4-D) and 600 mg l⁻¹ glutamine, and subcultured in the medium of the same composition for over 1 yr. This resulted in a mixed culture of embryogenic and non-embryogenic cells. When embryogenic cells were isolated and cultured independently, their capacity to form embryogenic aggregates was lost. Thus, the non-embryogenic cells present within a mixed culture system were essential to the formation of embryogenic aggregates. When embryogenic tissues were isolated and cultured independently on a high glutamine-containing (2400 mg l⁻¹) medium, dry weights and endogenous levels of glutamine increased, and the tissue could generate a large number of embryogenic aggregates. Amino acid analysis of embryogenic and non-embryogenic cells from the maintenance culture indicated a higher level of glutamine was present in the latter. The high endogenous level of glutamine in the non-embryogenic portion of mixed cell masses may be the supplier of glutamine for maintaining the embryogenic property of the tissues.     

Specificity of action of piperidylcholine derivatives as substrates of cholinesterases of various origin

The review deals with study of enzymologic properties of a novel highly specific acetylcholinesterase substrate, N-(β-acetoxyethyl) piperidinium iodomethylate (“piperidylcholine”), and its 30 derivatives that were tested as effectors of cholinesterases of mammals and various species of Pacific squids. It was proven for the first time that responsible for specificity of action was structure of cyclic ammonium grouping of the alcohol part of molecule of the ester substrate. Analysis of specificity is performed based on enzymatic hydrolysis parameters—activity of catalytic center of cholinesterases and bimolecular constant of the reaction rate that are determined at optimal and low substrate concentrations. Among the specially synthesized group of thioester compounds there is revealed one more highly specific acetylcholinesterase substrate—N-(β-acetoxyethyl) piperidinium.     

Interconnection of parameters of regulation system of lipid peroxidation and of morphophysiological parameters of mouse liver

A complex analysis of seasonal fluctuations of the mean group parameters of the system of regulation of lipid peroxidation has been performed in liver of Balb/c mice. Association of lipid characteristics and morphophysiological parameters is studied in the Balb/c mouse liver. An inter-connection is revealed between the liver index and the amount of lysoforms of phospholipids, the scale and character of the interconnection differing essentially depending on proportion of phos-phatidylcholine in mouse liver phospholipids.     

真菌类遗传学分析的知识结构教学

本文以认知结构理论为指导,讨论了真菌类遗传分析与高等动植物遗传分析的内在联系,认为利用这种内在联系进行教学可收到好的效果并说明了作者的具体教学过程。 Abstract:In the paper, the relationship between genetic analysis of Fungi and genetic analysis of high animal and plant was discussed.A good results were obtained when we adopted this method in the teaching.