Ragni M V
University of Pittsburgh Medical Center and Hemophilia Center of Western Pennsylvania, Pittsburgh, PA 15213-4306, USA.
Haemophilia. 2001 Jan;7 Suppl 1:28-35. doi: 10.1046/j.1365-2516.2001.00097.x.
Despite our best efforts to deceive the immune system, outwit pathogens, and improve upon the design of nature, there continues to be a need to improve the margin of safety of treatment for those with bleeding disorders. The current approach includes: (1) recombinant factor concentrates free of added proteins; (2) 'designer' factor molecules that enhance function and reduce immunogenicity; and (3) modulation of the immune system to suppress immune response in those who develop inhibitors. The hope is that through advances in our understanding of the coagulation and immune systems, treatment of haemophilia in the new millennium will be safer and less immunogenic. Currently available recombinant clotting factor concentrates include those produced: (1) with pasteurized human serum albumin in the cell culture medium as a stabilizer; (2) with bovine serum proteins in the cell culture medium; and (3) free of plasma derivatives. To the extent that current recombinant clotting factor concentrates contain even trace amounts of human or animal protein, there is continuing potential for transmission of nonenveloped viruses, including hepatitis A and parvovirus, and the theoretical potential for transmission of relatively unknown agents, such as prions (Creutzfeldt-Jakob disease or its variant). Second-generation recombinant factor concentrates that do not use human albumin as a stabilizer are currently in clinical trials, and third-generation recombinant factor concentrates currently in development take advantage of new strategies to achieve a 'protein-free' cell culture, purification, and final formulation. It is likely that improvement in safety and reduction in immunogenicity will require modification not only of antigenic structure but also of the immune response to coagulation proteins.
尽管我们竭尽全力欺骗免疫系统、智胜病原体并改进自然设计，但仍有必要提高出血性疾病患者治疗的安全边际。当前的方法包括：（1）不含添加蛋白的重组因子浓缩物；（2）增强功能并降低免疫原性的“设计型”因子分子；以及（3）调节免疫系统以抑制产生抑制剂者的免疫反应。人们希望，通过我们对凝血和免疫系统认识的进步，新千年的血友病治疗将更安全且免疫原性更低。目前可用的重组凝血因子浓缩物包括：（1）在细胞培养基中使用经巴氏消毒的人血清白蛋白作为稳定剂生产的；（2）在细胞培养基中使用牛血清蛋白生产的；以及（3）不含血浆衍生物的。就目前的重组凝血因子浓缩物甚至含有痕量人或动物蛋白而言，仍存在传播非包膜病毒（包括甲型肝炎病毒和细小病毒）的可能性，以及传播相对未知病原体（如朊病毒（克雅氏病或其变异型））的理论可能性。不使用人白蛋白作为稳定剂的第二代重组因子浓缩物目前正在进行临床试验，目前正在研发的第三代重组因子浓缩物利用新策略实现“无蛋白”细胞培养、纯化和最终制剂。安全性的提高和免疫原性的降低可能不仅需要对抗抗原结构进行修饰，还需要对凝血蛋白的免疫反应进行修饰。
