An oral TNFα inhibitor for inflammatory bowel disease

项目摘要 炎症性肠病是一组疾病(克罗恩病和溃疡性结肠炎) 给全世界数百万人带来了严重的发病率和残疾。尽管有多种生物制剂和 小分子被批准用于治疗，抗肿瘤坏死因子单抗仍是一线治疗。然而， 大约30%的患者由于中和抗药物抗体(ADA)而失去了这些药物的临床益处。 全身给药会导致免疫抑制，增加严重感染的风险。努力实现 研制肠道限制性口服抗肿瘤坏死因子抗体(为了方便和避免全身毒性)已经表明 治疗受益，但由于克服蛋白水解性肠道所需的高剂量，临床上并不可行 酶消化。DBT178是一种三聚化的14-D-氨基酸环肽，与 肿瘤坏死因子三聚体。它同时阻断可溶性和膜结合的肿瘤坏死因子活性，其效力是 领先的肿瘤坏死因子单抗，adalimumab(Humira®)，体外。D-肽是天然L多肽的手性镜像； 因此，它们基本上对酶蛋白分解是惰性的，并且在广泛的pH范围内是稳定的。因此，口头上 DBT178应原封不动地传输到IBD的部位(空肠、回肠和结肠)，以允许临床有效 给药。此外，DBT178的治疗性抗肿瘤坏死因子单抗的质量约为5%，应具有更大的 从肠腔粘膜向粘膜下组织穿透。口服DBT178有望最大限度地减少吸收 从肠道到门脉和体循环(从而限制潜在的全身毒性)，以及它对 蛋白水解性抗原处理将降低发展中和抗DBT178抗体的潜力。这个 这一阶段SBIR的目标是在两种小鼠模型上证明DBT178口服后的疗效 结肠炎。然而，由于该抑制物结合人肿瘤坏死因子，而不是小鼠肿瘤坏死因子，因此它不会在 常规IBD模型。因此，Aim 1优化了DBT178的口服给药，并测试了其对胃肠道的抑制作用 单次ip大剂量人肿瘤坏死因子后的毒性和全身炎症反应。AIM 2口试DBT178 利用B-hTNFA小鼠建立DSS诱导的急性结肠炎的专门模型，其中人肿瘤坏死因子α基因 插入到缺失的小鼠肿瘤坏死因子基因座后，在正常生理控制下表达。这 工作计划有一年的时间表。

Project Summary Inflammatory bowel disease is a group of disorders (Crohn’s disease and Ulcerative Colitis) that are associated with substantial morbidity and disability for millions of people worldwide. Although multiple biologic agents and small molecules are approved for the treatment, anti-TNF monoclonal antibodies remain first line therapy. Yet, clinical benefit from these agents is lost in ~30% of patients due to neutralizing anti-drug antibodies (ADAs). Systemic administration results in immunosuppression with heightened risk for serious infections. Efforts to develop gut-restricted oral anti-TNF antibodies (for convenience and to avoid systemic toxicity) have shown treatment benefit but have not been clinically feasible due to the high doses required to overcome proteolytic gut enzyme digestion. DBT178 is a trimerized 14 D-amino acid cyclic peptide that binds with exceptional affinity to the TNF trimer. It blocks both soluble and membrane-bound TNF activity and is 400-fold more potent than the leading TNF mAb, adalimumab (Humira®), in vitro. D-peptides are chiral mirror images of natural L-peptides; thus, they are essentially inert to enzymatic proteolysis and are stable over a broad pH range. Thus, orally administered DBT178 should transit intact to sites of IBD (jejunum, ileum and colon), permitting clinically effective dosing. In addition, DBT178 has ~5% the mass of therapeutic anti-TNF mAbs and should have a greater penetration from gut luminal mucosa to submucosal tissues. Oral DBT178 is expected to minimize absorption from gut to portal and systemic circulation (thereby limiting potential systemic toxicity), and its resistance to proteolytic antigen processing will reduce the potential for developing neutralizing anti-DBT178 antibodies. The goal of this Phase I SBIR is to demonstrate DBT178 efficacy following oral delivery in two mouse models of colitis. However, since this inhibitor binds human TNF, but not mouse TNF it will not be effective in conventional IBD models. Accordingly, Aim 1 optimizes DBT178 for oral delivery and tests its inhibition of GI toxicity and systemic inflammation following a single IP injection of high dose hTNF. Aim 2 tests oral DBT178 delivery in a specialized model of DSS-induced acute colitis using B-hTNFA mice, where the human TNFα gene is expressed under normal physiological control following its insertion into the deleted mouse TNF locus. This work plan has a 1-year timeline.