Centocor Research & Development, Inc., Division of Johnson & Johnson Pharmaceutical Research & Development, LLC, Malvern, Pennsylvania, USA.
Nat Biotechnol. 2011 Jul;29(7):615-24. doi: 10.1038/nbt.1903.
Preclinical and clinical studies conducted in the mid-1990s reported strong association and causality between the T-cell helper (T(H)) 1 inductor cytokine interleukin (IL)-12 and numerous immune-mediated disorders, which spurred the development of therapeutic agents targeting IL-12 function. One of the first to enter the clinic, ustekinumab, is a human monoclonal antibody (mAb) that binds to the p40 subunit of IL-12. Subsequent to the generation of ustekinumab, it was discovered that IL-23 also contains the p40 subunit. Thus, although ustekinumab was designed to target IL-12, it also modulates IL-23, a cytokine important to the development and/or maintenance of T(H)17 cells. Clinical observations established that IL-12/23p40 is integral to the pathologies of psoriasis, psoriatic arthritis and Crohn's disease. The molecular and cellular evaluations conducted in ustekinumab clinical programs have provided numerous insights into the pathologic processes of these disorders, illustrating how a novel molecular entity can contribute to our understanding of disease. The individual contributions of these cytokines to specific pathologies require investigation and clinical evaluation of the role of IL-12- and IL-23-specific inhibitors.
20 世纪 90 年代中期进行的临床前和临床研究报告称，辅助性 T 细胞（T(H)）1 诱导细胞因子白细胞介素（IL）-12 与许多免疫介导的疾病之间存在强烈的关联和因果关系，这促使开发了针对 IL-12 功能的治疗药物。最早进入临床的药物之一是乌司奴单抗，这是一种与人源化单克隆抗体（mAb），可与 IL-12 的 p40 亚基结合。乌司奴单抗生成后，人们发现 IL-23 也含有 p40 亚基。因此，尽管乌司奴单抗旨在靶向 IL-12，但它也调节了 IL-23，后者对于 T(H)17 细胞的发育和/或维持很重要。临床观察确立了 IL-12/23p40 是银屑病、银屑病关节炎和克罗恩病病理的重要组成部分。在乌司奴单抗临床项目中进行的分子和细胞评估为这些疾病的病理过程提供了许多见解，说明了一种新型分子实体如何有助于我们对疾病的理解。这些细胞因子对特定病理的个体贡献需要对 IL-12 和 IL-23 特异性抑制剂的作用进行研究和临床评估。
