Therapeutic targeting of the IL-12/23 pathways: generation and characterization of ustekinumab
Therapeutic targeting of the IL-12/23 pathways: generation and characterization of ustekinumab
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DOI：
10.1038/nbt.1903
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发表时间：
2011-07-01
影响因子：
46.9
通讯作者：
Mascelli, Mary A.
中科院分区：
文献类型：
--
作者：
Benson, Jacqueline M.;Sachs, Clifford W.;Mascelli, Mary A.
20世纪90年代中期进行的临床前和临床研究报告了T细胞辅助者(T-H)1诱导细胞因子IL-12与多种免疫介导性疾病之间的密切联系和因果关系，这刺激了针对IL-12功能的治疗药物的发展。首批进入临床的单抗之一是ustekinumab，它是一种与IL-12的p40亚单位结合的人类单抗。随着ustekinumab的产生，人们发现IL-23也含有p40亚基。因此，尽管ustekinumab被设计为针对IL-12，但它也调节IL-23，IL-23是一种对T(H)17细胞的发育和/或维持至关重要的细胞因子。临床观察证实，IL-12/23p40在银屑病、银屑病关节炎和克罗恩病的病理过程中是不可或缺的。在ustekinumab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，说明了一个新的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研究和临床评估IL-12和IL-23特异性抑制物的作用。
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.