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.

项目摘要 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 折磨约1.3％的美国人口。用批准的抗TNFα生物制剂阻断TNFα驱动的炎症 对于许多患者来说，这是一种有效的IBD治疗方法。但是，由于抗药物抗体导致的有效性丧失 （ADA）和诸如严重感染之类的毒性通常会导致抗TNFα生物制剂的中断。 我们已经开发了一种稳定的，抗蛋白酶的抗TNFαD肽DBT178 口服并完整地传递到IBD炎症特征的胃肠道（GI）部位。其他治疗性 其他赞助商评估的候选人已经证明 IBD患者的TNFα生物制剂。但是，这些药物是口服IBD疗法的主要原理的可行性 由于对胃肠道蛋白酶的效力和敏感性引起的高剂量要求高。 DBT178是通过镜像图像发现的〜8 kDa高潜力和特异性抗TNFαD肽 噬菌体显示。多个体外测定表明DBT178比 阻塞TNFα配体时的Adalimumab（Humira®）抗体：受体结合和TNFα介导的细胞杀伤。 与由L-氨基酸组成的天然胡椒体不同，D肽由镜像D-Amino组成 酸是其自然对应物的对映异构体。蛋白水解酶，包括在 已知肠道表现出手性特异性，因此D肽表现出对蛋白酶的显着稳定性。在老鼠中， 当通过口服饲料施用时，与DBT178紧密相关的“模型” D肽在凳子上是额外的 并且没有被吸收到全身循环中。因此，我们假设口服的DBT178将 抑制IBD的TNFα诱导的粘膜和粘膜下注射特征，而无需滥用 进入门户循环，系统性分布或全身免疫抑制。 此外，D肽也具有最小的免疫原性，因为它们对蛋白水解抗原具有抗性 通过抗原呈现细胞进行的处理，这是成功的免疫反应所必需的。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 在用当前抗TNFα生物制剂治疗的IBD患者中，观察到的效率丧失相关。 DBT178是一个承诺的候选产品，有可能破坏数十亿美元的抗TNFα 治疗牛皮癣，关节炎，葡萄膜炎和IBD的治疗景观。为了这 应用我们侧重于它提供方便，肠道限制和非免疫原性的潜力 替代当前批准的抗TNFα肠胃外生物制剂。 在此提案中，我们要求资金制造和制定非GMP批次DBT178的特征 它在模拟胃和肠道中的稳定性和活性，并评估其药代动力学和GI组织 口服给小鼠时穿透。我们还将表征其在非人类隐私中的免疫原性。