单克隆抗体在疾病治疗中的应用

单克隆抗体(单抗)技术与分子生物学技术的结合使重组嵌合抗体、人源化抗体和全人抗体的技术得到迅速发展.由于这些单抗带有人抗体的Fc片段,因此,这些抗体不仅能中和抗原,更重要的是能介导细胞毒作用和激活补体系统.这些抗体已被用于治疗某些疾病,如癌症、免疫性疾病、感染性疾病和器官移植排斥.随着大规模CHO细胞生产工艺的发展,越来越多的单抗将应用于临床.     

治疗性抗体药物研究与发展趋势

单克隆抗体技术的问世,使研究和生产治疗性单抗药物成为现实.随着基因工程技术的发展,新型的重组抗体技术也随之而生.人们可以利用DNA重组技术对鼠源抗体进行人源化改造、构建合成或半合成抗体库及噬菌体抗体库,从中筛选获得人源抗体,甚至利用转基因小鼠直接获得人源抗体.抗体药物发展的趋势也从鼠源、人一鼠嵌合、人源化到全人源.近年...     

全人源单克隆抗体现状及发展趋势(续)

4 技术平台全人源单抗是抗体工程技术发展的重要趋势.目前全人源单抗的研发技术主要有:B细胞永生化技术、噬菌体抗体库技术、转基因小鼠技术以及人源杂交瘤技术等.其中以噬菌体展示技术和转基因小鼠技术实际应用最广泛、最成功.     

新一代治疗抗体的研究进展

单抗（mAbs）目前是一类公认的治疗药物,有许多产品经批准上市用于诊断和治疗多种疾病,包括自身免疫疾病、移植排异反应、心血管疾病、炎性疾病、感染性疾病和肿瘤等,并且还存在巨大的发展空间.尽管其作为治疗制剂有着明显的优势,但是,常规抗体也具有明显的局限性.第一,它是大的和结构复杂的蛋白.首先,按照分子量标准,抗体属超大分子的物质,每个分子含有两条重蛋白链和两条轻链,并与糖分子杂乱地重叠在一起.由于其大分子特性,难以达到深藏于组织或膜中的靶.其次,由于其结构复杂,合成单抗之前通常需要从大鼠体内分离出抗体,然后进行人源化.人源化的过程非常复杂,需向鼠源性抗体中嵌入人体基因,编译出与人抗体的氨基酸序列相同的蛋白质片段,部分或全部取代鼠源性抗体中的蛋白.     

鼠源抗体的基因改造工程的发展与未来

抗体技术发展经历了三个阶段,杂交瘤技术出现使第一 代抗体-血清多克隆抗体,发展到第二代抗体-单克隆抗体, 其在理论和实践上的应用成为解决生物学、医学等许多重大 问题的手段。由于异源蛋白会引起人抗鼠抗体反应,而人源性单抗的生产有许多技术问题,因此随着基因工程技术的发展人们开始对鼠源单抗的基因进行种种改造,目的在于尽量减少抗体中的鼠源成份,但保留原特异性。主要包括合抗体 片段的杂合分子、鼠源单克隆抗体的人源化和小分子抗体。 嵌合抗体(Chimeric　Antibodies) 嵌合抗体是抗体基因工程的早阶段产物,由于抗体的特异性决定于…     

抗肿瘤单克隆抗体的临床应用

世界卫生组织预计,癌症将取代心血管病成为世界死亡人数最多的疾病。抗肿瘤药物的研发已成为制药领域的热点。单克隆抗体（单抗）能通过与肿瘤细胞上的特定靶标结合来杀死肿瘤细胞。迄今为止,已有14种抗肿瘤单抗获准上市。根据单抗的作用靶点不同,可将单抗分为抗表皮生长因子受体单抗、抗人表皮生长因子受体2单抗、抗血管内皮细胞生长因子抗体、抗白细胞分化抗原单抗。此文就以上几类抗肿瘤单抗的作用机制及临床应用进行综述。     

单克隆抗体治疗免疫疾病的研究进展

单克隆抗体是继疫苗和重组蛋白后最重要的一类生物制剂,已成功应用于治疗自身免疫性疾病和肿瘤等疾病中。单抗药物经历了从鼠源单抗、嵌合单抗到人源单抗和全人源单抗的发展过程。随着人源化单抗应用比例的提高,药物不良反应的发生率不断降低,治疗效果和安全性逐步提高,因此全人源单抗是单抗发展的趋势。本文阐述了四种有代表性的全人源单抗在免疫系统疾病治疗中的作用机制和临床评价。     

单克隆抗体研究进展

随着人们对抗体结构与功能的认识不断深入,抗体不仅在抵抗外来生物物质方面有着重要作用,而且利用它本身来防治疾病更是研究热点。单克隆抗体技术的问世,使得研究和生产单抗药物成为现实。本文就单抗药物的历史、现状、存在的问题及展望做一简要综述。     

抗体人源化技术研究进展

人源化单克隆抗体已日益广泛地应用于治疗以肿瘤为主的多种疾病.重组DNA技术使鼠源抗体的人源化改造得以实现.此文对抗体人源化技术的发展及面临的问题进行综述.     

抗人钠碘转运体单克隆抗体杂交瘤细胞系的建立与初步鉴定

目的 制备抗人钠碘转运体(NIS)单克隆抗体。方法 以人NIS蛋白质的二个片段(第2膜外段和第14f段)为抗原免疫小鼠，运用杂交瘤技术，制备鼠抗人NIS单克隆抗体(rhNIS MAb)，采用小鼠Ig亚类测定试剂条测定单抗的亚类，并通过ELISA、Western-blot、免疫组化技术等鉴定其特异性。结果 运用杂交瘤技术成功地制备出能稳定分泌抗人NIS单克隆抗体的细胞系。Western-blot分析表明：此单抗所识别的靶分子的相对分子量主要在97KD，免疫组化染色显示：甲状腺滤泡细胞基底膜上有棕黄色着色。结论 成功地制备出抗人NIS单克隆抗体，为NIS抗原-抗体的研究提供了新的工具，NIS单克隆抗体不仅可以应用于甲状腺、乳腺等领域的基础研究，而且可以用于临床，为甲状腺疾病的诊断和治疗提供切实保障。     

治疗性人源化单克隆抗体研究进展

目前正在研究中的生物技术药物有1/4以上是单克隆抗体药物,临床治疗中人抗鼠抗体反应(HAMA)的出现使鼠源性单克隆抗体的应用受到极大限制.因此,对于疗程长、需反复给药的单克隆抗体药物,人源化是其重要而必然的发展方向.现阶段,已有30余个通过细胞工程和基因工程制备的人源化抗体应用于临床,适应证包括变态反应性疾病、恶性肿瘤、器官移植排斥反应、心血管疾病、病毒感染等难治性疾病.此外尚有近百个人源化抗体药物正处在临床前或临床研究阶段.预计它们将在人类疾病的治疗中发挥重要作用.     

Preclinical and clinical safety of monoclonal antibodies

Owing to their unique specificity, monoclonal antibodies have provided a novel approach to the treatment of human diseases. Several types of antibodies against a diverse array of pharmacological targets have been marketed and many more are currently in clinical trials. Factors related to antigen expression, target pharmacology, and antibody effector functions can contribute to the adverse event profiles observed with monoclonal antibodies. Effective translation of information gained from preclinical research and safety studies into clinical development is a crucial step for successful development of monoclonal antibodies.     

Monoclonal antibodies as a strategy for pulmonary diseases.

Monoclonal antibodies have been used successfully to elucidate the roles of putative mediators of pulmonary disease. In particular, clinical trials with monoclonal antibodies directed against interleukin-5, IgE or CD4 yielded results that were critical in dissecting the pathophysiology of asthma; but, more importantly, fundamental changes in the discovery, manufacture and safety of monoclonal antibodies have reinforced the enormous potential of these agents in treating pulmonary diseases. An unprecedented number of monoclonal antibodies are in development for a variety of acute and chronic conditions. Moreover, whereas only two monoclonal antibodies had received regulatory approval from the United States Food and Drug Administration between 1986 and 1997, seven more have received approval since then. Indeed, monoclonal antibody therapy has come of age.     

Production, novel assay development and clinical applications of monoclonal antibodies

Since the advent of hybridoma technology 35 years ago, research on monoclonal antibodies has developed enormously. Monoclonal antibodies of mouse origin were the first to be produced and continue to be the most popular affinity reagents for investigating the proteome of all organisms. For their adaptability to a variety of biological assays monoclonal antibodies are key tools for basic research as well as for diagnosis and therapy of human diseases. Recently, the expanding demand of high-quality antibodies with better specificities has resulted in a significant improvement in traditional hybridoma production methods. Owing to the ability of these affinity reagents to selectively target tumour cells, cancer has been a major focus of programmes for monoclonal antibody development. This review focuses on patents related to the advances made in the monoclonal antibody manufacture, showing how the traditional production techniques were turned into alternative, faster and more effective methods. Other patents are focussed on new technologies in which monoclonal antibodies are employed for the development of high-performance screening assays. A conclusive series of patents is related to monoclonal antibodies which find application to the diagnosis and the treatment of specific cancer diseases such as haematological malignancies and solid tumours.     

嵌合抗体研究进展

单克隆抗体在疾病的诊断、治疗和预防中发挥着重要作用,但是在临床治疗中人抗鼠抗体反应的出现使鼠源性单克隆抗体的应用受到了很大限制.随着分子生物学、分子免疫学技术的飞速发展,抗体技术已发展到第三代抗体——基因工程抗体阶段,可利用基因工程技术对鼠源性抗体进行改造,保留或增强天然抗体的特异性和主要生物学活性,同时减少鼠源成分,以避免鼠源性单克隆抗体在临床应用方面的缺陷.此文就基因工程抗体中的重要组成部分嵌合抗体的研究进展做一综述.     

Trends in therapeutic monoclonal antibodies of cancer

Therapeutic monoclonal antibodies are increasingly applied in clinical application with great success. A variety of antibody products have been approved by the FDA since 1997. Furthermore, the industries have been paying more attention to and efforts in the field of antibody development than ever, suggesting the grand potential of the market and benefits. At present, many monoclonal antibodies have proven their therapeutic value in combination with established treatment for many diseases, as shown in FDA approved expanded indications. This old-fashioned immunotherapy exerts profound effects in many refractory and formidable diseases, especially cancers. With further understanding of the interaction between immune system and cancer, more target molecules were discovered and more promising therapeutic antibodies with improved effects will be feasible in the future. Regardless of initial development or ultimate approved drug, therapeutic monoclonal antibodies have always been associated with numerous patent applications. This review mainly focuses on potential therapeutic monoclonal antibodies in oncology and related antibody patents, and discusses the trend for antibody development and therapeutic applications in humans.     

Diagnosis of malignant melanoma with radiolabeled monoclonal antibodies: current status

Since the advent of the technique for preparation of monoclonal antibodies in 1975, these agents have been used in a variety of experimental procedures, including investigations into the structure of the human genome. The increasing availability of these highly specific antibodies has also spawned the development of kits for in vitro diagnosis of a number of diseases, and now radiolabeled monoclonal antibodies are undergoing clinical trials to assist in vivo diagnosis of several different cancers. We report our results in four representative cases comparing the efficacy of 111Indium-labeled antimelanoma, type 96.5, monoclonal antibodies against standard diagnostic imaging techniques at accurately diagnosing metastatic malignant melanoma lesions. In some cases the monoclonal antibody studies provided unequivocal evidence of the existence of metastases. In other cases no localization occurred, and we suggest plausible reasons for this failure and modifications of imaging technique to improve the performance. Overall, we believe monoclonal antibodies represent a promising new clinical aid in disease diagnosis which may ultimately permit direct targeting of therapeutic agents.     

Monoclonal antibodies: a morphing landscape for therapeutics

The concept of using antibodies as therapeutics to cure human diseases was postulated nearly 100 years ago by Paul Ehrlich and subsequently enabled by the discovery of hybridoma technology by Kohler and Milstein in 1975. While the use of monoclonal antibodies (mAbs) as drugs that can specifically target a disease‐associated antigen is compelling, it has taken a quarter century for these molecules to be adopted as bona fide therapeutic agents. Despite their slow pursuit in drug development during the pioneering years, it is now estimated that there are nearly 500 mAb‐based therapies in development. Major factors that have influenced the acceptance of monoclonal antibodies as therapeutics include their drug safety profiles, technological advancements for facilitating mAb discovery and development, and market success. Early on, it was demonstrated that antibodies could elicit clinical benefit by antagonizing a specific antigen without the common side effects that are prevalent with small chemical entities due to their nonspecific effects on homeostatic biochemical pathways. In addition, the significant technological advances that the biotechnology industry has established for developing and producing monoclonal antibodies at commercial scale in a more efficient and cost‐effective manner has broadly enabled their use as therapeutics. However, despite the beneficial pharmacologic advantages and technological advances, it has been the sheer market success that monoclonal antibody products have achieved over the past few years that has propelled their vast pursuit by the biopharmaceutical industry in light of their value‐creating potential. Here we provide an overview of the monoclonal antibody industry and discuss evolving technologies and strategies that are being pursued to overcome challenges in the changing marketplace. Drug Dev. Res. 67:781–789, 2006. © 2007 Wiley‐Liss, Inc.