抗肿瘤人源化抗体药物的研究进展

随着单克隆抗体技术的发展,治疗性抗体药物逐渐占据全球市场,主要应用于肿瘤治疗、抗移植排斥、自身免疫性疾病的治疗等。抗体药物可根据人源化程度不同,分为鼠源抗体、嵌合抗体、人源化抗体和全人源抗体。本文着眼于目前治疗性抗体药物研究热点,聚焦于抗肿瘤人源化抗体药物,结合已上市热点抗肿瘤人源化抗体药物实例,从抗体人源化技术以及人源化抗体生产的角度来阐述目前研究状况。同时,立足于国内外抗肿瘤人源化抗体药物的现状,分析未来发展趋势。     

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...     

人源化抗体

杂交瘤技术使抗人病原体或细胞的啮齿动物单克隆抗体得以产生，但在临床上的应用有限，依靠啮齿动物抗体的“人源化“蛋白质工程技术现已能产生用于治疗传染病，自身免疫病和肿瘤的各种抗体，人源化抗体的药物动力学有所改善，免疫原性降低，有利于临床使用。     

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.     

治疗性单克隆抗体的研究进展及其免疫偶联物的抗肿瘤应用

目前正在研究的生物技术药物有1/4是单克隆抗体类药物,治疗性抗体已成为生物制药业发展最快的领域之一,它们用于治疗如肿瘤、移植排斥、自身免疫病、心血管疾病、病毒感染等.在发展初期,鼠源单克隆抗体为人类疾病的研究起到了重大的推动作用,但其存在着严重的不足,单克隆抗体人源化已逐渐成为当前研究的热点.另外,将放射性物质、化疗药物以及生物毒素等与单克隆抗体偶联得到免疫偶联物,这些偶联物被单克隆抗体特异性地导向表达相应抗原细胞的表面,并发挥抗肿瘤效应,同时也降低了药物对正常组织的损伤.文中就有关单克隆抗体人源化的研究进展和抗肿瘤应用进行综述.     

单克隆抗体治疗制剂研究与应用

文本讨论了降低鼠单克隆抗体免疫原性的方法,采用嵌合抗体技术和互补决定区(CDR)稼接技术能使鼠源抗体部分人源化.此外,本文还介绍了治疗性单克隆抗体的研究现状.     

单克隆抗体人源化研究进展

目前单克隆抗体大多数是鼠源的，在临床重复给药的治疗过程中有许多副作用。由于技术限制，最好的解决方法就是研制人源化抗体，以代替 鼠源抗用于临床，本文概术了几种常用的异源单抗人源化的方法。     

单克隆抗体人源化研究进展

目前单克隆抗体大多数是鼠源的,在临床重复给药的治疗过程中有许多副作用。由于技术限制,最好的解决方法就是研制人源化抗体,以代替鼠源单抗用于临床。本文概述了几种常用的异源单抗人源化的方法。     

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.     

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.     

Humanized anti-EphB4 antibodies for the treatment of carcinomas and vasculogenesis-related diseases

The invention provides human, humanized or chimeric versions of anti-EphB4 mouse monoclonal antibodies that bind to the human EphB4 receptor tyrosine kinase. The described anti-EphB4 antibodies are derived from two murine mAbs #47 and #131 through framework shuffling and include those of the IgGl, IgG2, IgG3 or IgG4 human isotype. The patent further relates to pharmaceutical compositions, immunotherapeutic compositions and methods using therapeutic antibodies that bind to the human EphB4 antigen and that may induce phosphorylation and degradation of EphB4 and mediate antigen-dependent cell-mediated-cytotoxicity, complement-dependent cell-mediated cytotoxicity and/or apoptosis for the treatment of human malignancies and vasculogenesis-related disorders and diseases.     

抗体的发展过程及临床应用

单克隆抗体已经成为生物技术和制药领域的重要组成部分,目前多用基因工程制备嵌合抗体、人源化抗体、全人抗体。随着制备抗体技术的不断进步,其应用也越来越广泛,特别是抗体药物正迅速发展。近几年出现了许多具有里程碑意义的抗体药物,如程序性死亡受体1（PD-1）抗体、白介素17A（IL-17A）抗体、白介素5（IL-5）抗体、前蛋白转化酶枯草杆菌转化酶/可馨型9（PCSK9）抗体等,用于多种疾病的治疗,解决了不少临床难题。在现代医学中,单克隆抗体已经成为有效的治疗手段和诊断工具。本文结合中外文献主要介绍抗体的发展过程、抗体在临床方面的应用及近几年来FDA批准的具有重大意义的抗体药物。     

The use of antibodies to coagulation factors for anticoagulant therapy

Current treatments for preventing thrombotic diseases are associated with a significant risk of bleeding. Improved anticoagulant agents are therefore still required. The specificity and pharmacokinetics properties of monoclonal antibodies to coagulation factors allow novel anticoagulation approaches. Treatment with human antibodies or humanized mouse monoclonal antibodies should avoid unacceptable side effects due to immune response to the drug. Such antibodies were developed against three coagulation factor: Tissue factor (TF), Factor IX (FIX) and Factor VIII (FVIII). A fully humanized antibody was successfully derived from a mouse monoclonal antibodies to TF. In vivo studies with monoclonal antibodies to TF demonstrated efficient antithrombotic activity. Anti-TF antibodies may also prove useful in cardiovascular disorders and cancer, given the role of TF in these diseases. Mouse and human monoclonal antibodies to FIX were also efficient to prevent thrombosis in animal models of venous and arterial thrombosis and in stroke. A humanized anti-FIX antibody was tested in phase I study in healthy volunteers. The pharmacokinetics of the antibody were determined by the rapid formation of stable complexes with newly synthesised FIX. Human anti-FVIII antibodies inhibiting only partially FVIII activity were recently described. Investigations in mice have established that treatment with such anti-FVIII antibodies is efficient to prevent deep vein thrombosis. Given the low concentration of FVIII in plasma and the long half-life of antibody, treatment with anti-FVIII antibody could be very convenient, allowing one administration every month. Altogether, monoclonal antibodies to coagulation factor appear as promising novel antithrombotic drugs.     

人源抗体的研究进程及其在控制病毒感染中的作用

多年来,研究人员一直在研究单克隆抗体在病毒性疾病中的临床应用。由于鼠源单克隆抗体可能会引发患者的免疫反应,降低其疗效,故研究人员相继开发了嵌合抗体、改型抗体、噬菌体抗体及利用基因工程方法改造植物和动物产生人源抗体以应用于临床治疗。人源抗体在控制多种病毒感染性疾病方面已取得一些进展,并将发挥重要作用。     

利妥昔单抗治疗恶性淋巴瘤的进展

利妥昔单抗（人源化CD20单克隆抗体，商品名美罗华）是首个批准用于治疗表达CD20恶性淋巴省的单克隆抗体，广泛应用于低度恶性非雷奇金琳巴瘤（NHL）、侵袭性NHL，亦试用于霍奇金淋巴瘤（HL）及其他B细胞性恶性肿瘤。刊蚤昔单抗联合细胞毒性药物的疗效已在B细胞NHL的有关临床试验中得到证实。目前该药已被批准用于侵袭性淋巴瘤和惰性淋巴瘤的一线治疗，其维持治疗滤泡性淋巴瘤亦得出鼓舞人心的结果．利妥昔单抗已成为治疗B细胞性恶性淋巴瘤的重要手段之一。     

Monoclonal antibody form and function: Manufacturing the right antibodies for treating drug abuse

Drug abuse continues to be a major national and worldwide problem, and effective treatment strategies are badly needed. Antibodies are promising therapies for the treatment of medical problems caused by drug abuse, with several candidates in preclinical and early clinical trials. Monoclonal antibodies can be designed that have customized affinity and specificity against drugs of abuse, and because antibodies can be designed in various forms, in vivo pharmacokinetic characteristics can be tailored to suit specific clinical applications (eg, long-acting for relapse prevention, or short-acting for overdose). Passive immunization with antibodies against drugs of abuse has several advantages over active immunization, but because large doses of monoclonal antibodies may be needed for each patient, efficient antibody production technology is essential. In this minireview we discuss some of the antibody forms that may be effective clinical treatments for drug abuse, as well as several current and emerging production systems that could bridge the gap from discovery to patient use.     

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.