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， 约占美国人口的1.3%。使用获批的抗TNF α生物制剂阻断TNFα驱动的炎症 对许多患者来说是有效的IBD治疗方法。然而，由于抗药抗体导致的疗效丧失 ADA和毒性（如严重感染）通常导致抗TNF α生物制剂停药。 我们开发了一种稳定的、抗蛋白酶的抗TNF α D肽DBT 178， 口服并完整递送至IBD的炎症特征的胃肠道（GI）部位。其它治疗 由其他赞助商评估的候选人已经证明了口服抗- IBD患者中的TNFα生物制剂。然而，这些药剂作为口服IBD治疗剂主要是不可行的。 这是由于低效力和对GI蛋白酶的敏感性导致的高剂量要求。 DBT 178是通过镜像发现的~8 kDa高效特异性抗TNF α D肽， 噬菌体展示多个体外测定已经证明，DBT 178实质上比 阿达木单抗（修美乐®）抗体阻断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，包括那些发现于 已知肠具有手性特异性，因此D-肽对蛋白酶表现出显著的稳定性。在大鼠中， 经口灌胃给药时，与DBT 178密切相关的“模型”D-肽在粪便中完整排泄 并且不被吸收到体循环中。因此，我们假设口服给予DBT 178将 抑制TNFα诱导IBD特征性粘膜和粘膜下炎症，而无相关吸收 进入门静脉循环、全身分布或全身免疫抑制。 此外，D-肽也是最低免疫原性的，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对成功的免疫反应是必要的处理。预计 肠道限制和低免疫原性表明，DBT 178不太可能诱导抗药抗体（ADA）或 在约30%接受当前抗TNF α生物制剂治疗的IBD患者中观察到相关疗效丧失。 DBT 178是一种有前途的候选产品，有可能破坏价值数十亿美元的抗TNF α药物。 银屑病、炎症性关节炎、葡萄膜炎和IBD的治疗前景。为此 应用我们已经集中在它的潜力，以提供一个方便的，肠道限制和非免疫原性的口服 目前获批的抗TNF α胃肠外生物制剂的替代品。 在本提案中，我们申请资金用于生产和配制非GMP批次的DBT 178，表征 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GI组织 当口服给小鼠时，我们还将描述其在非人灵长类动物中的免疫原性。