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
- 来源:
- 关键词:AffinityAmino AcidsAntibodiesAntibody ResponseAntigen-Presenting CellsApoptosisArthritisBindingBiologicalBiological AssayBiological ProductsBiophysicsBlood CirculationCell Culture TechniquesCell LineCharacteristicsChronicChronic DiseaseClinicalColitisColonCrohn&aposs diseaseCultured CellsCyclic Amino AcidsCyclic PeptidesDevelopmentDigestionDiseaseDoseDrug KineticsEnzymesEpithelial CellsExhibitsExposure toFecesFundingGastrointestinal tract structureGoalsGoldHigh Pressure Liquid ChromatographyHistocytochemistryHospitalizationHumanHumiraImageImmune responseImmunosuppressionInfectionInflammationInflammatoryInflammatory Bowel DiseasesInjectionsIntellectual PropertyIntestinesKnock-inLeadLigandsLiquid substanceMediatingMembraneMethodologyMethodsModelingMonitorMonoclonal AntibodiesMorbidity - disease rateMucous MembraneMusOpportunistic InfectionsOralOral AdministrationOutcomePatientsPenetrationPeptide HydrolasesPeptidesPermeabilityPersonsPhage DisplayPharmaceutical PreparationsPhasePhase I Clinical TrialsPlasmaPopulationPrevalencePropertyProteolysisPsoriasisRattusResistanceRiskSiteSmall Business Innovation Research GrantSolubilitySpecificityStomachSurface Plasmon ResonanceTNF geneTherapeuticTissuesToxic effectToxicologyTransgenic MiceUlcerative ColitisUrineUveitisabsorptionadalimumabanalytical methodantigen processingbasebiophysical propertiescell killingchemically induced colitisdesigndisabilityeffective therapyenantiomerexperienceexperimental studygastrointestinalileumimmunogenicimmunogenicityimmunoregulationin vitro Assayin vivoin vivo Modelinhibitorinnovationjejunumnonhuman primatenovel therapeuticsparenteral administrationpeptide Lreceptor bindingrisk benefit ratioside effectsmall moleculesystemic toxicitytherapeutic candidatetumor necrosis factor-alpha inhibitor
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。
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
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
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)
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)
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
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: