Pap T
Institut für Experimentelle Muskuloskelettale Medizin, Universitätsklinikum Münster, Domagkstr. 3, 48149 Münster.
Z Rheumatol. 2010 Feb;69(1):73-8. doi: 10.1007/s00393-009-0595-3.
As mediators of inflammation, cytokines contribute significantly to both the development and the extent of the inflammatory response in rheumatoid arthritis (RA). In addition, they regulate the differentiation of various cells involved in the pathogenesis of this disease. Tumour necrosis factor alpha (TNF alpha), interleukin (IL)-1 and IL-6 constitute prominent examples of such inflammatory cytokines and have been shown to play an important role in RA. As a consequence, the use of recombinant antibodies targeting these cytokines has revolutionized the treatment of RA. However, a considerable number of RA patients do not respond adequately to therapy with such biologics. Based on this notion, this article summarizes current trends in the design and development of monoclonal antibodies against inflammatory mediators. These include the identification of alterative target structures for anti-cytokine therapies, the specific modification of the antigen-binding CDR of therapeutic antibodies to reduce immunogenicity, alterations of the Fc part and the development of modified antibody fragments to improve the pharmacokinetics and to avoid non-specific immune reactions. Beyond that, efforts are undertaken to optimize the cost of these therapies.
作为炎症介质，细胞因子在类风湿关节炎（RA）炎症反应的发生发展及程度方面都起着重要作用。此外，它们还调节参与该疾病发病机制的各种细胞的分化。肿瘤坏死因子α（TNFα）、白细胞介素（IL）-1和IL-6是此类炎性细胞因子的突出例子，并且已证明它们在类风湿关节炎中发挥重要作用。因此，使用靶向这些细胞因子的重组抗体彻底改变了类风湿关节炎的治疗方式。然而，相当数量的类风湿关节炎患者对这类生物制剂治疗反应不佳。基于这一观念，本文总结了针对炎症介质的单克隆抗体设计与开发的当前趋势。这些趋势包括确定抗细胞因子疗法的替代靶标结构、对治疗性抗体的抗原结合互补决定区（CDR）进行特异性修饰以降低免疫原性、改变Fc部分以及开发修饰的抗体片段以改善药代动力学并避免非特异性免疫反应。除此之外，人们还在努力优化这些疗法的成本。
