Developing the required biomarkers that define IL-23R target engagement and effect on downstream signaling for late stage drug development and early clinical proof-of-concept
开发所需的生物标志物来定义 IL-23R 靶标参与以及对下游信号传导的影响,以用于后期药物开发和早期临床概念验证
基本信息
- 批准号:9348501
- 负责人:
- 金额:$ 97.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-09-30 至 2019-04-30
- 项目状态:已结题
- 来源:
- 关键词:Adverse effectsAffectAntibodiesArteriesBindingBiologicalBiological AvailabilityBiological MarkersBiological ProductsBiopsy SpecimenBloodBody Weight decreasedCardiovascular systemCellsCharacteristicsChronic DiseaseClinicalClinical TrialsColitisColonCrohn&aposs diseaseDataDevelopmentDigestionDiseaseDisease modelDisulfidesDoseDrug ControlsDrug Delivery SystemsDrug KineticsEconomic BurdenEnvironmentEventExcisionExposure toGastrointestinal tract structureHealth Care CostsHospitalizationHumanIncidenceInfectionInflammatory Bowel DiseasesInjectableInjection of therapeutic agentInterleukin-12Intestinal DiseasesIntestinesIntravenous infusion proceduresLeadLengthLifeMeasurementMethodsModelingMonoclonal AntibodiesMucositisMucous MembraneNatureOralOutcomePathologyPathway interactionsPatientsPeptidesPharmaceutical ChemistryPharmaceutical PreparationsPharmacodynamicsPharmacologyPharmacotherapyPhasePlayPopulationProductionRattusReactionRegimenResearchResistanceRoleSafetySideSignal TransductionSiteSmall Business Innovation Research GrantTNF geneTechniquesTechnologyTherapeuticTherapeutic Monoclonal AntibodiesTissuesTranslatingTranslationsUlcerative ColitisUnited StatesWeightcardiovascular risk factorcompliance behaviorcostdesigndrug candidatedrug developmentearly onsetexperiencegastrointestinalimprovedin vivoinnovationinterleukin-23neutralizing antibodynext generationpatient populationpharmacodynamic biomarkerpre-clinicalpreventprogramsprotein protein interactionreceptorresponsescaffold
项目摘要
Abstract
Developing the required biomarkers that define IL-23R target engagement and effect on downstream
signaling for late-stage drug development and early clinical proof-of-concept.
Inflammatory bowel disease (IBD) affects about 0.5% of the world's population. Due to its early onset and lack
of an adequate cure, this disease requires lifelong treatment. IBD affects the gastrointestinal (GI) tract and
manifests as two subtypes: Crohn's disease (CD) and ulcerative colitis (UC). In recent years, anti-TNF biological
agents have transformed the treatment of IBD, but these are not ideal drugs, requiring administration by injection,
and in some instances hospitalization for intravenous infusion. These agents have numerous side effects,
including increased infection rates; additionally, anywhere from 10-30% of patients either lose response (through
the production of neutralizing antibodies) or become intolerant (e.g., site reactions). Long half-lives of injected
antibodies, which can result in TNF blockade over sustained periods, can exacerbate these issues and make it
hard to control drug exposure to minimize safety issues. Although current anti-TNF drugs possess similar modes
of action, switching from one agent to another is an established treatment approach for patients who become
unresponsive or intolerant. Stelara (ustekinumab) targets both the IL-12 and IL-23 pathways and is efficacious
in Phase III Crohn's disease clinical trials in TNF-resistant patients. However, there is some concern about
cardiovascular safety events, as illustrated by the removal from the market of briakinumab (which also targets
IL-12 and IL-23) due, in part, to increased cardiovascular risk. IL-23 is produced locally in the intestine and plays
a fundamental role controlling intestinal mucosal inflammation. Hence, selectively modulating the IL-23 pathway
locally in diseased tissue is the preferred strategy. Such an approach would provide high concentrations of drug
in diseased tissue and block IL-23 function locally in the intestine. During the Phase I SBIR , we developed a
potent (2 nM), orally stable antagonist (PN1140) of the IL-23 receptor (IL-23R) that is efficacious when orally
delivered in a TNBS-induced model of colitis. PN1140 prevented body weight loss, reduced the colon weight-to-
length ratio, and (most importantly) improved colon macroscopic pathology. PN1140 was predominantly
restricted to GI tissue with minimal systemic exposure. The overall objective of this Phase II SBIR proposal is to
develop methods for characterizing in vivo target engagement, including pharmacokinetic and pharmacodynamic
methods to characterize the binding of PN1140 to IL-23R in various compartments and how binding affects
downstream biomarkers and efficacy. These biomarkers will be used to aid compound and dose selections, and
to provide early-stage clinical proof-of-concept. The specific objectives are to: 1) Develop the required target
engagement methods to enable quantification of binding of PN1140 to IL-23R-bearing cells; 2) Identify the
required pharmacodynamics biomarkers that would reflect the downstream biological changes upon target
engagement; and 3) Correlate target engagement and pharmacodynamics biomarkers with efficacy readouts in
TNBS models of colitis in rats. This Phase 2 SBIR program is supported by a team that has a track record in the
oral delivery of constrained peptides, a proven capacity in translating early-stage research to clinical outcomes,
a group of scientific and clinical advisors with significant experience in IBD, and the appropriate research
environment. In this Phase II SBIR proposal, we describe the development of the appropriate biomarkers that
will establish early proof-of-concept and the effective human dose range through an assessment of target
engagement and pharmacologic activity in early-stage human trials. These are important steps towards our
ultimate objective of demonstrating clinical benefit in late-stage clinical trials. These biomarkers will permit the
assessment of mechanism-specific and disease-related parameters in blood, fecal, and/or colon biopsy samples.
摘要
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(1)
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 }}
David Y Liu其他文献
Rusfertide Analog-PN23114 As a Hepcidin Mimetic Provides Efficacy Benefits in Conjunction with Phlebotomy in Mouse Model for Hereditary Hemochromatosis
- DOI:
10.1182/blood-2022-171139 - 发表时间:
2022-11-15 - 期刊:
- 影响因子:
- 作者:
Roopa Taranath;Celino Dion;Ashok Bhandari;David Y Liu - 通讯作者:
David Y Liu
Mechanism of Systemic Iron Regulation and Hematocrit Control By Hepcidin Peptidomimetics in Pre-Clinical Models
临床前模型中铁调素肽模拟物的全身铁调节和血细胞比容控制机制
- DOI:
10.1182/blood-2020-141670 - 发表时间:
2020 - 期刊:
- 影响因子:20.3
- 作者:
R. Taranath;L. Mattheakis;Li Zhao;L. Lee;J. Tovera;Jingsong Zhao;Xiaoli Cheng;David Y Liu - 通讯作者:
David Y Liu
Iron Restricted Erythropoiesis Under Hepcidin Mimetic Treatment (PN23114) Improved Disease Parameters in a Mouse Model for Sickle Cell Disease
- DOI:
10.1182/blood-2023-182472 - 发表时间:
2023-11-02 - 期刊:
- 影响因子:
- 作者:
Roopa Taranath;Li Zhao;Gregory Bourne;Ramesh R Bhatt;Scott Plevy;David Y Liu;Ashok Bhandari - 通讯作者:
Ashok Bhandari
David Y Liu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 }}
{{ truncateString('David Y Liu', 18)}}的其他基金
Developing the required biomarkers that define ferroportin target engagement and impact on downstream signaling for clinical translation
开发所需的生物标志物来定义铁转运蛋白靶点参与和对临床转化下游信号传导的影响
- 批准号:
9762166 - 财政年份:2016
- 资助金额:
$ 97.05万 - 项目类别:
Hepcidin Mimetics for the Treatment of Iron Overload Diseases
用于治疗铁过载疾病的铁调素模拟物
- 批准号:
9202712 - 财政年份:2016
- 资助金额:
$ 97.05万 - 项目类别:
相似海外基金
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 97.05万 - 项目类别:
Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 97.05万 - 项目类别:
Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 97.05万 - 项目类别:
Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 97.05万 - 项目类别:
Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 97.05万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 97.05万 - 项目类别:
Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 97.05万 - 项目类别:
Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 97.05万 - 项目类别:
Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
- 批准号:
23K00129 - 财政年份:2023
- 资助金额:
$ 97.05万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
- 批准号:
2883985 - 财政年份:2023
- 资助金额:
$ 97.05万 - 项目类别:
Studentship