Validation of a Novel NF-kB Inhibitor in Inflammatory Bowel Disease

描述(由申请人提供)：人类炎症性肠病(IBD)、克罗恩病和溃疡性结肠炎影响着100多万美国人，但仍存在大量未得到满足的医疗需求。核因子？？B转录因子的激活是IBD慢性炎症发生和持续的中心事件。TheraLogics，Inc.一直处于核因子B研究的前沿，并拥有与包括TLX1423在内的新型核因子B抑制物肽相关的知识产权。TLX1423是一个由8-赖氨酸(8K)蛋白转导结构域(PTD)和I？B激酶(IKK)抑制序列组成的多肽，称为“NEMO结合域(NBD)”。与其他核因子βB抑制剂相比，TLX1423具有抑制激活的核因子βB(慢性炎症的标志)的优点，但不抑制参与基本细胞过程的基础核因子βB的活性，从而与毒性相关。在第一阶段，我们在开发TLX1423作为治疗IBD的药物方面取得了重要的里程碑，并在《免疫学杂志》上发表了这些发现。我们证实了TLX1423转导到细胞和组织中。在体实验中，TLX1423可抑制回肠内毒素激活的核因子？B，但不能抑制Peyer‘s结的基础核因子？？B。经TLX1423全身治疗的IL-10-/-小鼠的结肠炎症状明显改善，固有层中的核因子B活性降低。在第一阶段，我们还证明了在两个实验性IBD模型中，直肠内给药TLX1423可以改善肠道炎症。治疗IBD的理想药物是口服。然而，对炎症肠道的药物输送仍然是一个挑战，主要原因有两个：1)缺乏能够在局部传递并抑制其在肠道免疫细胞中的靶点的高效免疫调节剂，2)缺乏将这些物质携带到炎症部位且在胃肠道中降解最少的载体。为这项第二阶段提案组建的多学科团队已经为这些障碍开发了创新的解决方案。这将是将毒性降至最低、增加患者依从性和改善生活质量的重要进步。为了应对这些挑战，我们开发了基于微乳(ME)的递送系统，适用于TLX1423的局部给药，并通过肠道释放策略，将多肽靶向胃肠道的炎症区域。我们的初步数据显示，与游离相比，油包水(w/o)MES中的PTD多肽可以有效地传递到小鼠的大肠中。 PTD多肽。TheraLogics已聘请CMC、监管和临床顾问将这一第二阶段计划的结果转化为下一阶段，包括GMP制造、GLP安全/毒性研究和IND提交。

DESCRIPTION (provided by applicant): The human inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis, affect over one million Americans and significant unmet medical needs still exist. Activation of NF??B transcription factors are central events in the initiation and perpetuation of chronic inflammation in IBD. TheraLogics, Inc., have been at the forefront of NF??B research and hold intellectual property pertaining to novel NF??B inhibitor peptides including TLX1423. TLX1423 is a peptide comprised of a 8 lysine (8K) protein transduction domain (PTD) with an I?B kinase (IKK) inhibitory sequence, "NF??B essential modulator" (NEMO) binding domain (NBD). Compared to other NF??B inhibitors, TLX1423 has the advantages of inhibiting activated NF??B, a hallmark of chronic inflammation, but not inhibiting basal NF??B activity, involved in fundamental cellular processes thus correlating with toxicity. During phase 1, we achieved important milestones in the development of TLX1423 as a therapy for IBD and published these findings in the Journal of Immunology. We demonstrated transduction of TLX1423 into cells and tissues. In-vivo, TLX1423 inhibited LPS-activated NF??B in the ileum, but did not inhibit basal NF??B in Peyer's patches. IL-10-/- mice treated systemically with TLX1423 demonstrated amelioration of established colitis and decreased NF??B activation in the lamina propria. In phase 1, we also demonstrated that intrarectal administration of TLX1423 results in amelioration of intestinal inflammation in two experimental IBD models. The ideal therapeutic agent to treat IBD would be administered by mouth. However, drug delivery to the inflamed intestine remains a challenge for two main reasons: 1) lack of highly effective immunomodulatory agents that can be delivered locally and inhibit their targets in intestinal immune cells and, 2) lack of vehicles to carry these agents to the site of inflammation with minimal degradation in the GI tract. The multidisciplinary team assembled for this phase 2 proposal has developed innovative solutions to these hurdles. This would be an important advancement to minimize toxicity, increase patient compliance, and improve quality of life. To address these challenges, we have developed microemulsion (ME)- based delivery systems suitable for local administration of TLX1423, and via enteric release strategies, target the peptide to inflamed regions of the GI tract. We show preliminary data that PTD peptides in water-in-oil (w/o) MEs are efficiently delivered to the large intestine in mice as compared to free PTD peptides. TheraLogics has enlisted CMC, regulatory and clinical consultants to translate results of this phase 2 program into the next phases, including GMP manufacturing, GLP safety/toxicity studies, and an IND submission.