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

基本信息

  • 批准号:
    10547573
  • 负责人:
  • 金额:
    $ 30.15万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
项目总结 炎症性肠病(IBD)、克罗恩病(CD)和溃疡性结肠炎(UC)都是令人衰弱的疾病, 困扰着大约1.3%的美国人口。批准的抗肿瘤坏死因子α生物制品阻断肿瘤坏死因子α引起的炎症 对于许多患者来说,这是一种有效的IBD治疗方法。然而,由于抗药物抗体而导致的疗效丧失 (ADAS)和严重感染等毒性通常会导致停用抗肿瘤坏死因子α生物制品。 我们已经开发出一种稳定的、抗蛋白酶的、抗肿瘤坏死因子α的D-肽,DBT178,它的设计是为了 口服,并原封不动地输送到IBD特有的炎症部位的胃肠道(GI)。其他治疗方法 由其他赞助商评估的候选人已经证明了口服抗病毒药物的活动证据 炎症性肠病患者的肿瘤坏死因子α生物制品。然而,这些药物主要作为口服IBD治疗药物并不可行。 由于低效性和对胃肠道蛋白水解酶的敏感性,对剂量的要求很高。 DBT178是通过镜像技术发现的一种8 kDa的高效、特异的抗肿瘤坏死因子αD-肽 噬菌体展示。多项体外试验表明,DBT178的效力明显高于 阿达利单抗(HUMIRA®)阻断肿瘤坏死因子α配体:受体结合和肿瘤坏死因子α介导的细胞杀伤 与由L氨基酸组成的自然肽不同,D-肽由镜像D-氨基酸组成 酸是其天然对映体的对映体。蛋白水解酶,包括那些在 Gut,已知具有手性特异性,因此D-肽对蛋白水解酶表现出显著的稳定性。在老鼠身上, 口服给药时,一种与DBT178密切相关的“模型”D-肽在大便中被完整地排出 并且没有被吸收到体循环中。因此,我们假设口服DBT178会 抑制肿瘤坏死因子α诱导的炎性肠病粘膜和粘膜下炎性反应 进入门静脉循环、全身分布或全身免疫抑制。 此外,D-肽也是最小的免疫原性,因为它们对蛋白水解性抗原具有抵抗力。 由抗原提呈细胞进行的处理,这是成功的免疫反应所必需的。预期 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 在接受当前抗肿瘤坏死因子α生物制剂治疗的IBD患者中,约有30%的患者观察到相关的疗效丧失。 DBT178是一种很有前途的候选产品,有可能扰乱价值数十亿美元的抗肿瘤坏死因子α 治疗牛皮癣、炎症形式的关节炎、葡萄膜炎和IBD的治疗景观。为了这个 应用我们重点研究了它提供方便、肠道受限和非免疫原性口服的潜力 目前批准的抗肿瘤坏死因子α肠外生物制品的替代品。 在这份提案中,我们申请资金来制造和配制非GMP批次的DBT178,特征 在模拟胃液和肠液中的稳定性和活性,并评价其药代动力学和胃肠道组织 对小鼠口服时的渗透性。我们还将鉴定其在非人类灵长类动物中的免疫原性。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

ALAN F WAHL其他文献

ALAN F WAHL的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

相似海外基金

Double Incorporation of Non-Canonical Amino Acids in an Animal and its Application for Precise and Independent Optical Control of Two Target Genes
动物体内非规范氨基酸的双重掺入及其在两个靶基因精确独立光学控制中的应用
  • 批准号:
    BB/Y006380/1
  • 财政年份:
    2024
  • 资助金额:
    $ 30.15万
  • 项目类别:
    Research Grant
Quantifying L-amino acids in Ryugu to constrain the source of L-amino acids in life on Earth
量化 Ryugu 中的 L-氨基酸以限制地球生命中 L-氨基酸的来源
  • 批准号:
    24K17112
  • 财政年份:
    2024
  • 资助金额:
    $ 30.15万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Molecular recognition and enantioselective reaction of amino acids
氨基酸的分子识别和对映选择性反应
  • 批准号:
    23K04668
  • 财政年份:
    2023
  • 资助金额:
    $ 30.15万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Basic research toward therapeutic strategies for stress-induced chronic pain with non-natural amino acids
非天然氨基酸治疗应激性慢性疼痛策略的基础研究
  • 批准号:
    23K06918
  • 财政年份:
    2023
  • 资助金额:
    $ 30.15万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Molecular mechanisms how arrestins that modulate localization of glucose transporters are phosphorylated in response to amino acids
调节葡萄糖转运蛋白定位的抑制蛋白如何响应氨基酸而被磷酸化的分子机制
  • 批准号:
    23K05758
  • 财政年份:
    2023
  • 资助金额:
    $ 30.15万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Design and Synthesis of Fluorescent Amino Acids: Novel Tools for Biological Imaging
荧光氨基酸的设计与合成:生物成像的新工具
  • 批准号:
    2888395
  • 财政年份:
    2023
  • 资助金额:
    $ 30.15万
  • 项目类别:
    Studentship
Collaborative Research: RUI: Elucidating Design Rules for non-NRPS Incorporation of Amino Acids on Polyketide Scaffolds
合作研究:RUI:阐明聚酮化合物支架上非 NRPS 氨基酸掺入的设计规则
  • 批准号:
    2300890
  • 财政年份:
    2023
  • 资助金额:
    $ 30.15万
  • 项目类别:
    Continuing Grant
Structurally engineered N-acyl amino acids for the treatment of NASH
用于治疗 NASH 的结构工程 N-酰基氨基酸
  • 批准号:
    10761044
  • 财政年份:
    2023
  • 资助金额:
    $ 30.15万
  • 项目类别:
Lifestyle, branched-chain amino acids, and cardiovascular risk factors: a randomized trial
生活方式、支链氨基酸和心血管危险因素:一项随机试验
  • 批准号:
    10728925
  • 财政年份:
    2023
  • 资助金额:
    $ 30.15万
  • 项目类别:
Single-molecule protein sequencing by barcoding of N-terminal amino acids
通过 N 端氨基酸条形码进行单分子蛋白质测序
  • 批准号:
    10757309
  • 财政年份:
    2023
  • 资助金额:
    $ 30.15万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了