Podolsky Daniel K
University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.
Dig Dis. 2009;27(3):366-9. doi: 10.1159/000228575. Epub 2009 Sep 24.
Even as further refinements of anti-TNF continue to emerge, new biologics targeting alternative mechanisms are progressing through clinical development programs and offer the opportunity for categorically new therapeutics in the years ahead. Several of these target regulatory cytokines occupy important nodal positions in the intricate pathways mediating immune and inflammatory injury. A number of agents which antagonize the IL-12/IL-23 axis appear to offer promise. The apparent efficacy of these anti-cytokine agents has served as a stimulus for development of therapeutics that inhibits the signaling pathway common to their action. In addition to the focus of new biologic development on additional components of the cytokine network, other biologics target mechanisms of recruitment of various key cell populations to mucosa involved in inflammatory bowel disease. Natalizumab is already approved for clinical use and targets alpha4 with proven efficacy in Crohn's disease. A more specific antibody designated finds alpha4beta7 (also known as MAdCAM) trials has had efficacy in ulcerative colitis and probable efficacy in Crohn's disease. Efforts continue to exploit increasing understanding of the mechanisms necessary for T cell activation, and most especially co-stimulatory molecules to intervene in immune-related injury. A chimeric protein encompassing CTLA4 and an immunoglobulin tail (abatacept) has yielded promising results. Another mechanistic strategy to intervene with recruitment of key leukocytes to sites of disease activity has focused on members of the chemokine family that appear to be especially critical to the intestinal mucosa. In summary, the expanding knowledge of mechanisms that contribute to the pathogenesis of inflammatory bowel diseases has yielded a wealth of new potential targets and the results of the variety of agents currently being developed offer promise for a rich mix of next-generation biologics.
即使抗TNF药物的进一步改进不断涌现，针对其他作用机制的新型生物制剂也在通过临床开发项目取得进展，并为未来几年带来全新治疗方法的机会。其中一些针对调节性细胞因子的靶点在介导免疫和炎症损伤的复杂通路中占据重要节点位置。一些拮抗IL-12/IL-23轴的药物似乎颇具前景。这些抗细胞因子药物的明显疗效刺激了抑制其共同作用信号通路的治疗方法的开发。除了新生物制剂开发聚焦于细胞因子网络的其他组成部分外，其他生物制剂还针对各种关键细胞群体募集至炎症性肠病相关黏膜的机制。那他珠单抗已获批临床使用，其靶点为α4，在克罗恩病中已证实具有疗效。一种更具特异性的名为靶向α4β7（也称为黏膜地址素细胞黏附分子）的抗体在溃疡性结肠炎试验中显示出疗效，在克罗恩病中可能也有疗效。人们继续努力利用对T细胞激活所必需机制的深入理解，尤其是共刺激分子，来干预免疫相关损伤。一种包含CTLA4和免疫球蛋白尾部的嵌合蛋白（阿巴西普）已取得了有前景的结果。另一种干预关键白细胞募集至疾病活动部位的机制策略聚焦于趋化因子家族成员，这些成员似乎对肠道黏膜尤为关键。总之，对炎症性肠病发病机制的不断扩展的认识产生了大量新的潜在靶点，目前正在开发的各种药物的结果为丰富多样的下一代生物制剂带来了希望。
