Tangri S, LiCalsi C, Sidney J, Sette A
Epimmune Incorporated, 5820 Nancy Ridge Drive, San Diego, CA-92121, USA.
Curr Med Chem. 2002 Dec;9(24):2191-9. doi: 10.2174/0929867023368647.
One challenge associated with the clinical use of protein therapeutics destined for chronic administration is the potential for the development of unwanted anti-drug immune reactions. The molecular basis for this reactivity is the binding of peptide fragments (epitopes) derived from the breakdown of the protein drug to the HLA receptors expressed by the patient's immune cells. If these epitopes are recognized as "foreign" by the immune system, specific helper T lymphocytes (HTL), are activated, which initiate and direct the formation of antibodies against the protein drug. These antibodies can bind and neutralize the protein drug, resulting in either decreased efficacy or total ineffectiveness of the drug. Moreover, various safety concerns, such as allergic reactions and other adverse events, are also frequently associated with the formation of anti-drug antibodies. Herein, we describe the development of "ImmunoStealth", an integrated bioinformatics, biochemical and cellular immunology approach that specifically addresses the issue of unwanted immune responses against protein therapeutics. Unwanted HTL epitopes are identified using in silico sequence analysis methods and high throughput in vitro biochemical evaluations and thereafter confirmed using cellular immunogenicity assays. The "offending" epitopes within the drug are then rationally modified to alter their HLA binding capacity, and thus render them non-recognizable by the immune system. This technology will ultimately facilitate the design of safer, more potent and more economical drugs.
与用于长期给药的蛋白质疗法临床应用相关的一个挑战是可能产生不良的抗药物免疫反应。这种反应性的分子基础是蛋白质药物分解产生的肽片段（表位）与患者免疫细胞表达的HLA受体结合。如果这些表位被免疫系统识别为“外来物”，特定的辅助性T淋巴细胞（HTL）就会被激活，从而启动并指导针对蛋白质药物的抗体形成。这些抗体可以结合并中和蛋白质药物，导致药物疗效降低或完全失效。此外，各种安全问题，如过敏反应和其他不良事件，也经常与抗药物抗体的形成有关。在此，我们描述了“ImmunoStealth”的开发，这是一种综合的生物信息学、生物化学和细胞免疫学方法，专门解决针对蛋白质疗法的不良免疫反应问题。使用计算机序列分析方法和高通量体外生化评估来识别不需要的HTL表位，然后使用细胞免疫原性测定进行确认。然后对药物中的“有害”表位进行合理修饰，以改变其HLA结合能力，从而使其不被免疫系统识别。这项技术最终将有助于设计更安全、更有效和更经济的药物。
