A Next-Generation Therapeutic for Treatment of TNFα-mediated Inflammatory Diseases

治疗 TNFα 介导的炎症性疾病的下一代疗法

• 批准号: 10547573
• 负责人: ALAN F WAHL
• 金额: $ 30.15万
• 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: 2022-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10547573
• 关键词: Affinity; Amino Acids; Antibodies; Antibody Response; Antigen-Presenting Cells; Apoptosis; Arthritis; Binding; Biological; Biological Assay; Biological Products; Biophysics; Blood Circulation; Cell Culture Techniques; Cell Line; Characteristics; Chronic; Chronic Disease; Clinical; Colitis; Colon; Crohn' s disease; Cultured Cells; Cyclic Amino Acids; Cyclic Peptides; Development; Digestion; Disease; Dose; Drug Kinetics; Enzymes; Epithelial Cells; Exhibits; Exposure to; Feces; Funding; Gastrointestinal tract structure; Goals; Gold; High Pressure Liquid Chromatography; Histocytochemistry; Hospitalization; Human; Humira; Image; Immune response; Immunosuppression; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injections; Intellectual Property; Intestines; Knock-in; Lead; Ligands; Liquid substance; Mediating; Membrane; Methodology; Methods; Modeling; Monitor; Monoclonal Antibodies; Morbidity - disease rate; Mucous Membrane; Mus; Opportunistic Infections; Oral; Oral Administration; Outcome; Patients; Penetration; Peptide Hydrolases; Peptides; Permeability; Persons; Phage Display; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Plasma; Population; Prevalence; Property; Proteolysis; Psoriasis; Rattus; Resistance; Risk; Site; Small Business Innovation Research Grant; Solubility; Specificity; Stomach; Surface Plasmon Resonance; TNF gene; Therapeutic; Tissues; Toxic effect; Toxicology; Transgenic Mice; Ulcerative Colitis; Urine; Uveitis; absorption; adalimumab; analytical method; antigen processing; base; biophysical properties; cell killing; chemically induced colitis; design; disability; effective therapy; enantiomer; experience; experimental study; gastrointestinal; ileum; immunogenic; immunogenicity; immunoregulation; in vitro Assay; in vivo; in vivo Model; inhibitor; innovation; jejunum; nonhuman primate; novel therapeutics; parenteral administration; peptide L; receptor binding; risk benefit ratio; side effect; small molecule; systemic toxicity; therapeutic candidate; tumor necrosis factor-alpha inhibitor

PROJECT SUMMARY Inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC) are debilitating disorders that afflict ~1.3% of the U.S. population. Blockade of TNFα-driven inflammation with approved anti-TNFα biologics has been an effective IBD treatment for many patients. However, loss of efficacy due to anti-drug antibodies (ADAs) and toxicities such as serious infections often lead to discontinuation of anti-TNFα biologics. We have developed a stable, protease-resistant, anti-TNFα D-peptide, DBT178, that is designed to be taken orally and delivered intact to gastrointestinal (GI) sites of inflammation characteristic of IBD. Other therapeutic candidates evaluated by other sponsors have already demonstrated proof of activity for orally administered anti- TNFα biologics in IBD patients. However, these agents have not been feasible as oral IBD therapeutics primarily due to high dosing requirements resulting from low potency and sensitivity to GI proteases. DBT178 is an ~8 kDa highly potent and specific anti-TNFα D-peptide that was discovered via mirror-image phage display. Multiple in vitro assays have demonstrated that DBT178 is substantially more potent than adalimumab (Humira®) antibody at blocking TNFα ligand:receptor binding and TNFα-mediated cell killing. Unlike natural peptides composed of L-amino acids, D-peptides are composed of mirror-image D-amino acids and are the enantiomers of their natural counterparts. Proteolytic enzymes, including those found in the gut, are known to exhibit chiral specificity, thus D-peptides demonstrate remarkable stability to proteases. In rats, when administered by oral gavage, a “model” D-peptide closely related to DBT178 was excreted intact in stool and was not absorbed into systemic circulation. Therefore, we hypothesize that orally administered DBT178 will inhibit TNFα -induced mucosal and submucosal inflammation characteristic of IBD without associated absorption into the portal circulation, systemic distribution, or systemic immunosuppression. Furthermore, D-peptides are also minimally immunogenic since they are resistant to the proteolytic antigen processing carried out by antigen presenting cells that is necessary for successful immune responses. Expected gut restriction and low immunogenicity suggest that DBT178 is unlikely to induce anti-drug antibodies (ADA) or the associated loss of efficacy observed in ~30% of IBD patients treated with current anti-TNFα biologics. DBT178 is a promising product candidate with the potential to disrupt the multi-billion-dollar anti-TNFα therapeutics landscape for treatment of psoriasis, inflammatory forms of arthritis, uveitis and IBD. For this application we have focused on its potential to provide a convenient, gut restricted and non-immunogenic oral alternative to the currently approved anti-TNFα parenteral biologics. In this proposal, we request funding to manufacture and formulate a non-GMP batch of DBT178, characterize its stability and activity in simulated gastric and intestinal fluids, and assess its pharmacokinetics and GI tissue penetration when given orally to mice. We will also characterize its immunogenicity in non-human primates.

项目概要 炎症性肠病 (IBD)、克罗恩病 (CD) 和溃疡性结肠炎 (UC) 是使人衰弱的疾病， 困扰约 1.3% 的美国人口。使用批准的抗 TNFα 生物制剂阻断 TNFα 驱动的炎症 已成为许多 IBD 患者的有效治疗方法。然而，由于抗药物抗体而失去功效 （ADA）和严重感染等毒性通常会导致抗 TNFα 生物制剂的停用。 我们开发了一种稳定、抗蛋白酶、抗 TNFα D 肽 DBT178，旨在 口服并完整递送至具有 IBD 炎症特征的胃肠道 (GI) 部位。其他治疗 其他赞助商评估的候选人已经证明了口服抗- IBD 患者的 TNFα 生物制剂。然而，这些药物主要作为口服 IBD 治疗方法尚不可行。 由于对胃肠道蛋白酶的效力低且敏感性低而导致高剂量要求。 DBT178 是通过镜像发现的约 8 kDa 高效且特异性的抗 TNFα D 肽 噬菌体展示。多项体外试验表明 DBT178 比 阿达木单抗 (Humira®) 抗体可阻断 TNFα 配体：受体结合和 TNFα 介导的细胞杀伤。 与由 L-氨基酸组成的天然肽不同，D-肽由镜像 D-氨基酸组成 酸并且是其天然对应物的对映体。蛋白水解酶，包括存在于 已知 D 肽表现出手性特异性，因此 D 肽对蛋白酶表现出显着的稳定性。在老鼠身上， 当通过口服管饲给药时，与 DBT178 密切相关的“模型”D 肽在粪便中完整排出 且不被吸收进入体循环。因此，我们假设口服 DBT178 将 抑制 TNFα 诱导的 IBD 粘膜和粘膜下炎症特征，且无相关吸收 进入门静脉循环、全身分布或全身免疫抑制。 此外，D 肽也具有最低限度的免疫原性，因为它们对蛋白水解抗原具有抗性 由抗原呈递细胞进行的处理是成功免疫反应所必需的。预期的 肠道限制和低免疫原性表明 DBT178 不太可能诱导抗药物抗体 (ADA) 或 在约 30% 接受当前抗 TNFα 生物制剂治疗的 IBD 患者中观察到相关的疗效丧失。 DBT178是一种有前途的候选产品，有可能颠覆价值数十亿美元的抗TNFα药物 治疗牛皮癣、炎症性关节炎、葡萄膜炎和炎症性肠病的治疗前景。为了这 我们重点关注其提供方便、肠道限制且非免疫原性口服药物的潜力。 目前批准的抗 TNFα 肠外生物制剂的替代品。 在此提案中，我们请求资金来生产和配制非 GMP 批次的 DBT178，其特征 其在模拟胃液和肠液中的稳定性和活性，并评估其药代动力学和胃肠组织 给小鼠口服时具有渗透性。我们还将表征其在非人类灵长类动物中的免疫原性。