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。     

抗体偶联药物的技术现状和展望

抗体偶联药物（antibody drug conjugate,ADC）通常由抗体通过链接体与毒素小分子偶联而成,同时具备抗体的高靶向性和小分子药物的高活性,使之作为一种新兴的靶向治疗手段,在肿瘤治疗领域展现出了优秀的疗效和潜力,成为药物研发领域的新热点。目前全球已有14款ADC药物获批上市,处于临床研究阶段的ADC候选药物分子超过140个。为了进一步提高ADC药物的安全性和有效性,近年来涌现出了各种新颖的技术。本文对ADC药物分子的关键元素,包括抗体、链接体、毒素小分子以及偶联技术等方面的最新研究进展进行总结,并讨论其优缺点。期望这些讨论能够帮助增加对ADC药物研究和开发更加系统的理解,为研发出更加高效和安全的ADC药物带来一些思考。     

抗体偶联药物国内研发现状及企业布局分析

抗体偶联药物(antibody-drug conjugates,ADC)由单克隆抗体和小分子细胞毒药物通过连接子偶联而成,因在血液瘤、实体瘤等临床治疗中被证明是一种极有前景的技术手段,已经成为国内外抗体药物研发的新热门方向.系统阐述了ADC药物开发及工业化生产中的核心五要素,对国内ADC的研发管线进行了梳理,并对参与A...     

ADC药物的抗体组成及其作用靶点研究进展*

抗体药物偶联物(antibody-drug conjugates,ADC)是一类由单克隆抗体和小分子细胞毒性药物通过连接子偶联而成的新型生物治疗药物。与传统的细胞毒药物相比,ADC具有靶向性强、毒副作用小等优势,在临床上展现较好的治疗潜力。其中,抗体部分通过与肿瘤细胞表面的靶向抗原结合,精准地将小分子细胞毒性药物递送至肿瘤部位,从而实现肿瘤特异性杀伤效果,是影响ADC疗效的核心要素之一。对近年来ADC药物中抗体的组成及其作用靶点的研究进展进行了综述。     

抗肿瘤抗体-药物偶联物的临床研究进展

个体化靶向治疗已成为肿瘤临床治疗的新趋势.抗肿瘤靶向药物与传统的细胞毒性化疗药物相比具有特异性高、选择性强和非细胞毒性等优点,近年来发展迅速.抗体-药物偶联物(ADCs)属于抗肿瘤靶向药物,由抗体、“弹头”药物(细胞毒性药物)通过链分子连接而成.ADCs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.目前,FDA已批准2种ADC药物上市,即Mylotarg和Adcetris,有多种ADCs处于Ⅰ～Ⅲ期临床试验阶段,取得了显著的临床效果.本文概述了以美登素,卡奇霉素、Auristantin等三种细胞毒性药物为“弹头”药物的ADCs药物的临床研究状况及临床试验结果,为ADCs的研究和应用提供参考.     

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。     

Her2抗体与MMAE偶联物的制备及生物活性研究

目的:制备Her2抗体与海兔毒素MMAE的偶联物,检测该抗体-药物偶联药物(ADC)对于乳腺癌细胞的抑制作用。方法:将Her2抗体通过一个可降解的linker与小分子毒素(MMAE)连接起来,形成抗体药物偶联物(ADC)。通过细胞学试验检测Her2抗体-MMAE偶联物对于肿瘤细胞抑制、细胞凋亡和细胞周期的作用。结果:通过优化偶联条件,ADC偶联率达80%以上。肿瘤细胞生长抑制的实验显示ADC药物的IC50比单克隆抗体的IC50明显降低,作用效果更加明显。细胞凋亡和细胞周期实验结果表明,ADC药物72h诱导细胞凋亡率高达40%,单一抗体药物则仅为20%。结论:该ADC药物具有很好的抑制乳腺癌细胞的作用。     

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。     

简述量子点与抗体的偶联方法

量子点是一种具有独特光学性质的半导体纳米材料,表面带有功能基团的水溶性量子点可与抗体偶联,作为荧光探针用于多种生物学研究。根据量子点表面所修饰的物质不同,偶联方法可分为共价偶联与非公价偶联两大类。本研究主要对量子点与抗体的偶联方法进行简单介绍。     

聚乙二醇修饰小分子药物的研究进展

以高聚物作为载体,携带各种活性化合物组成药物释放系统,在现代医疗中发挥了巨大的作用。高分子偶联物不仅可以改变药物的药动学特征,还可以通过偶联特异性的物质使药物具有主动靶向性。目前研究最广泛的高分子载体是聚乙二醇。聚乙二醇通过与肽链、抗体、酶等活性化合物偶联,可以提高药物溶解度,延长循环半衰期,减少非特异性摄取,增加靶向性。已有很多聚乙二醇修饰的药物上市,也有很多尚处于临床研究阶段。大部分聚乙二醇化药物的临床研究表明,聚乙二醇修饰的药物确实可以提高药效、降低毒副作用。但关于聚乙二醇修饰小分子药物的设计依然需要进一步研究和完善。我们主要讨论聚乙二醇修饰小分子药物的设计和应用。     

Recent advances in the study of Kaposi's sarcoma-associated herpesvirus replication and pathogenesis

It has now been over twenty years since a novel herpesviral genome was identified in Kaposi's sarcoma biopsies. Since then, the cumulative research effort by molecular biologists, virologists, clinicians, and epidemiologists alike has led to the extensive characterization of this tumor virus, Kaposi's sarcoma-associated herpesvirus(KSHV; also known as human herpesvirus 8(HHV-8)), and its associated diseases. Here we review the current knowledge of KSHV biology and pathogenesis, with a particular emphasis on new and exciting advances in the field of epigenetics. We also discuss the development and practicality of various cell culture and animal model systems to study KSHV replication and pathogenesis.     

The structure, reproduction and taxonomy of Vidalia and Osmundaria (Rhodophyta, Rhodomelaceae)

Comprises species occurring mostly in subtidal habitats in tropical, subtropical and warm-temperate areas of the world. An analysis of the type species, V. spiralis (Sonder) Lamouroux ex J. Agardh, a species from Australia, establishes basic characters for distinguishing species in the genus. These characters are (1) branching patterns of thalli, (2) flat blades that may be spiralled on their axis, (3) width of the blade, (4) primary or secondary derivation of sterile and fertile branchlets and (5) position of sterile and fertile branchlets on the thalli. Application of the latter two characters provides an important basic method for separation of species into three major groups. Osmundaria , a genus known only in southern Australia, was studied in relation to Vidalia , and its separation from the Vidalia assemblage is not accepted. Species of Vidalia therefore are transferred to the older genus name, Osmundaria. Two new species, Osmundaria papenfussii and Osmundaria oliveae are described from Natal. Confusion in the usage of the epithet, Vidalia fimbriala Brown ex Turner has been clarified, and Vidalia gregaria Falkenberg, described as an epiphyte on Osmundaria pro/ifera Lamouroux, is revealed to be young branches of the host, Osmundaria prolifera.     

New or rare chromosome counts in Artemisia L. (Asteraceae, Anthemideae) and related genera from Kazakhstan

Fifteen chromosome counts of six Artemisia taxa and one species of each of the genera Brachanthemum, Hippolytia, Kaschgaria, Lepidolopsis and Turaniphytum are reported from Kazakhstan. Three of them are new reports, two are not consistent with previous counts and the remainder are confirmations of very scarce (one to four) earlier records. All the populations studied have the same basic chromosome number, x = 9, with ploidy levels ranging from 2x to 6x. Some correlations between ploidy level, morphological characters and distribution are noted.     

肝癌中HBV和HCV基因和抗原的分布及意义

采用原位分子杂交方法检测HCV RNA及HBV X基因;采用免疫组织化学方法研究HCV核心抗原,非结构区C33c抗原及HBxAg在肝细胞肝癌中的定位及分布.结果表明(1)HCV RNA、HBV X基因在肝细胞肝癌组织检出率分别为40%(55/136)和82%(112/136).HCV RNA定位于癌细胞的胞浆内,阳性细胞呈散在、灶状及弥漫分布三种形式;HBV X基因在肝癌细胞中的分布呈胞浆型、核型及核浆型,阳性细胞也呈上述三种分布形式;(2)HCV C33c抗原、核心抗原在肝细胞肝癌中的阳性率为81%(133/164)及86%(141/164).C33c抗原定位于癌细胞及肝细胞的胞浆内;核心抗原既定位于癌细胞核中,又可定位于胞浆中.C33c抗原阳性细胞以灶状分布为主;而核心抗原阳性细     

Selection with two alleles and complete dominance

For a plant selection model with frequency-independent viabilities, fertilities and selfing rates, it is shown that apart from global fixation, for certain parameter combinations a protected polymorphism and facultative fixation (either allele may become fixed according to initial frequencies) may both occur. Facultative fixation requires different selling rates for the dominant and recessive type. Protection of the polymorphism requires resource allocation for male and female function. In this connection the problem of purely genetically caused population extinction is discussed.
For general frequency dependence and regular segregation, the chances for establishment of a completely recessive gene are compared to those of a completely dominant gene. It is proven that the process of establishment of the recessive gene, despite a fitness advantage, may be considerably endangered by drift effects if random mating prevails. The recessive gene may reach the same effectivity in establishment as a dominant gene, only if the recessive homozygote mates exclusively with its own type during the period of establishment.