An oral TNFα inhibitor for inflammatory bowel disease

口服 TNFα 抑制剂治疗炎症性肠病

• 批准号: 10603230
• 负责人: GRANT H RISDON
• 金额: $ 30万
• 依托单位: D BIOTHERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-23 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10603230
• 关键词: Affinity; Antibodies; Binding; Biological Products; Blood Circulation; Chronic Disease; Clinical; Colitis; Colon; Crohn' s disease; Cultured Cells; Cyclic Amino Acids; Cyclic Peptides; Digestion; Disease; Disease model; Dose; Enzymes; Genes; Goals; Hospitalization; Human; Humira; Image; Immunosuppression; In Vitro; Infection; Inflammatory; Inflammatory Bowel Diseases; Intellectual Property; Intraperitoneal Injections; Mediating; Membrane; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Mucous Membrane; Mus; Oral; Oral Administration; Outcome; Patients; Penetration; Peptides; Permeability; Persons; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Physiological; Prevalence; Proteolysis; Resistance; Risk; Site; Small Business Innovation Research Grant; Symptoms; TNF gene; Testing; Therapeutic; TimeLine; Tissues; Toxic effect; Transgenic Mice; Tumor Necrosis Factor Receptor; Ulcerative Colitis; Work; absorption; adalimumab; antigen processing; dextran sulfate sodium induced colitis; disability; experience; ileum; inhibitor; innovation; jejunum; murine colitis; peptide L; risk benefit ratio; small molecule; systemic inflammatory response; systemic toxicity; tumor necrosis factor-alpha inhibitor

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.

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）， 全世界有数百万人患有严重的发病率和残疾。虽然多种生物制剂和 小分子被批准用于治疗，抗TNF α单克隆抗体仍然是一线治疗。然而， 由于中和性抗药抗体（ADA），约30%的患者丧失了这些药物的临床获益。 全身给药导致免疫抑制，严重感染的风险增加。努力 开发肠道限制性口服抗TNF α抗体（为了方便和避免全身毒性）已显示 但由于克服消化道蛋白水解所需的高剂量， 酶消化DBT 178是一种三聚化的14 D-氨基酸环肽，其以异常的亲和力结合至 TNF α三聚体。它阻断可溶性和膜结合的TNF α活性，其效力是对照组的400倍。 领先的TNF α mAb，阿达木单抗（Humira®），体外。D-肽是天然L-肽的手性镜像; 因此，它们对酶促蛋白水解基本上是惰性的，并且在宽的pH范围内是稳定的。因此，口头 施用的DBT 178应完整地转运至IBD的部位（空肠、回肠和结肠），允许临床有效的 剂量。此外，DBT 178具有约5%的治疗性抗TNF α mAb的质量，并且应该具有更大的生物活性。 从肠腔粘膜渗透到粘膜下组织。口服DBT 178预期可最大限度地减少吸收 从肠道到门静脉和体循环（从而限制潜在的全身毒性），以及其对 蛋白水解抗原加工将降低产生中和性抗DBT 178抗体的可能性。的 该I期SBIR的目的是在两种小鼠模型中证明口服递送后DBT 178的功效， 结肠炎然而，由于该抑制剂结合人TNF α，但不结合小鼠TNF α，因此其在治疗中将不是有效的。 传统IBD模型。因此，目标1优化了DBT 178的口服递送，并测试了其对GI的抑制 在单次IP注射高剂量hTNF α后的毒性和全身炎症。目的2测试口服DBT 178 使用B-hTNFA小鼠在DSS诱导的急性结肠炎的专门模型中递送，其中人TNFα基因 在其插入缺失的小鼠TNF α基因座后在正常生理控制下表达。这 工作计划有一个为期一年的时间轴。