Dimitrov Dimiter S, Marks James D
NCI-Frederick, National Institutes of Health, Frederick, MD, USA.
Methods Mol Biol. 2009;525:1-27, xiii. doi: 10.1007/978-1-59745-554-1_1.
Antibody-based therapeutics currently enjoy unprecedented success, growth in research and revenues, and recognition of their potential. It appears that the promise of the "magic bullet" has largely been realized. There are currently 22 monoclonal antibodies (mAbs) approved by the United States Food and Drug Administration (FDA) for clinical use and hundreds are in clinical trials for treatment of various diseases including cancers, immune disorders, and infections. The revenues from the top five therapeutic antibodies (Rituxan, Remicade, Herceptin, Humira, and Avastin) nearly doubled from $6.4 billion in 2004 to $11.7 billion in 2006. During the last several years major pharmaceutical companies raced to acquire antibody companies, with a recent example of MedImmune being purchased for $15.6 billion by AstraZeneca. These therapeutic and business successes reflect the major advances in antibody engineering which have resulted in the generation of safe, specific, high-affinity, and non-immunogenic antibodies during the last three decades. Currently, second and third generations of antibodies are under development, mostly to improve already existing antibody specificities. However, although the refinement of already known methodologies is certainly of great importance for potential clinical use, there are no conceptually new developments in the last decade comparable, for example, to the development of antibody libraries, phage display, domain antibodies (dAbs), and antibody humanization to name a few. A fundamental question is then whether there will be another change in the paradigm of research as happened 1-2 decades ago or the current trend of gradual improvement of already developed methodologies and therapeutic antibodies will continue. Although any prediction could prove incorrect, it appears that conceptually new methodologies are needed to overcome the fundamental problems of drug (antibody) resistance due to genetic or/and epigenetic alterations in cancer and chronic infections, as well as problems related to access to targets and complexity of biological systems. If new methodologies are not developed, it is likely that gradual saturation will occur in the pipeline of conceptually new antibody therapeutics. In this scenario we will witness an increase in combination of targets and antibodies, and further attempts to personalize targeted treatments by using appropriate biomarkers as well as to develop novel scaffolds with properties that are superior to those of the antibodies now in clinical use.
基于抗体的疗法目前取得了前所未有的成功，研究和收入不断增长，其潜力也得到了认可。“神奇子弹”的前景似乎已基本实现。目前，有22种单克隆抗体（mAb）已获美国食品药品监督管理局（FDA）批准用于临床，还有数百种正处于治疗各种疾病（包括癌症、免疫紊乱和感染）的临床试验阶段。排名前五的治疗性抗体（利妥昔单抗、类克、赫赛汀、修美乐和阿瓦斯汀）的收入从2004年的64亿美元几乎翻了一番，增至2006年的117亿美元。在过去几年中，各大制药公司竞相收购抗体公司，最近阿斯利康以156亿美元收购MedImmune就是一个例子。这些治疗和商业上的成功反映了抗体工程的重大进展，在过去三十年中已产生了安全、特异、高亲和力且无免疫原性的抗体。目前，第二代和第三代抗体正在研发中，主要是为了提高现有抗体的特异性。然而，尽管对已知方法的改进对于潜在临床应用肯定非常重要，但在过去十年中，在概念上并没有出现类似抗体文库、噬菌体展示、结构域抗体（dAb）和抗体人源化等那样的新进展。那么一个基本问题是，是否会像10到20年前那样，研究范式再次发生变化，还是目前已开发方法和治疗性抗体逐步改进的趋势将继续下去。尽管任何预测都可能被证明是错误的，但似乎需要在概念上有新的方法来克服癌症和慢性感染中由于基因或/和表观遗传改变导致的药物（抗体）耐药性这一基本问题，以及与靶点可达性和生物系统复杂性相关的问题。如果不开发新方法，概念上新的抗体疗法的研发可能会逐渐饱和。在这种情况下，我们将看到靶点与抗体的联合使用会增加，并会进一步尝试通过使用合适的生物标志物使靶向治疗个性化，以及开发具有优于目前临床使用抗体特性的新型支架。
