Immune cell targeting of corticosteroids transforms the treatment of severe, chronic inflammatory diseases
皮质类固醇的免疫细胞靶向改变了严重慢性炎症性疾病的治疗
基本信息
- 批准号:10625527
- 负责人:
- 金额:$ 99.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-06-22 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdrenal Cortex HormonesAffinityAnti-Inflammatory AgentsAntibodiesAntibody-drug conjugatesAsthmaAutoimmune DiseasesAwardBiologicalBiological MarkersBiological ProductsBlack raceBudesonideCellsChronicChronic DiseaseClinicClinicalClinical TreatmentConfidential InformationDataDevelopmentDiseaseDoseDose LimitingEligibility DeterminationEngineeringExposure toGlucocorticoidsGoalsHandHematopoieticHumanImmuneImmune TargetingImmune systemImmunologicsIn VitroInflammationInflammatoryLaboratoriesLeadLungMacaca fascicularisMaximum Tolerated DoseMeasurableMeasuresModelingMonoclonal AntibodiesMusPatientsPeripheral Blood Mononuclear CellPharmaceutical PreparationsPharmacotherapyPhasePriceProcessProteinsRequest for ProposalsRiskRisk ManagementRunningSafetySmall Business Innovation Research GrantSpecificitySteroidsStressSurveysTestingTherapeuticTherapeutic EffectTherapeutic EquivalencyTissuesToxic effectToxicologyTranscriptasthmaticasthmatic patientchronic inflammatory diseaseclinical efficacycommercializationcytokinedesigndisorder controldrug discoveryefficacy evaluationhealthy volunteerimmunogenicityin vivolead candidatemanufacturenew therapeutic targetnonhuman primatepanaceapatient populationpharmacokinetics and pharmacodynamicspharmacologicphase I trialphase II trialpreventprogramsside effectstandard of caretargeted agenttargeted deliverytranscriptomicsuptake
项目摘要
Glucocorticoids (GC) are a class of drugs with overwhelming anti-inflammatory activities. However, dose
limiting toxicities (DLT) caused by systemic GC exposure prevent GC from being a true panacea in the
management of inflammatory disease. This Direct SBIR Phase 2 proposal requests support for a novel
therapeutic that targets delivery of GC to the immune system, which will reduce DLT and allow for the long term
and high dose use of GC in the treatment of inflammation. ImmuNext has established the technical merit,
feasibility, proof of concept and commercial potential of this antibody-targeted, immune-specific steroid
conjugate. We have achieved specific and direct targeting of GC to the immune system with INX200, an
antibody-drug conjugate (ADC) of an Fc-silent, fully humanized immune-targeting mAb conjugated through a
cleavable linker to budesonide. Importantly, targeting GC with INX200 results in superior potency and reduced
toxicity when compared to free GC. We have shown that INX200: 1) broadly targets the immune system with
minimal exposure outside the hematopoietic compartment, 2) leverages an immune-targeting mAb that itself
(unconjugated) possesses no known immunologic activities and acts exclusively as a targeting agent, 3) rapidly
internalizes allowing for robust and efficient uptake of the GC thereby providing superior loading of GC into
immune cells, 4) is therapeutically equivalent at 1/10th the dose, and has substantially longer PD compared to
free GC, 5) has minimal off target activity and reduced toxicity compared to free GC due to its specific immune
system targeting, 6) is suitable for SC administration and 7) is an attractive therapeutic for the treatment of GC-
dependent asthma because of the unmet GC need in this patient population.
The Specific Aims of this Phase 2 application are as follows. 1) Assess the lead ADC INX200 and multiple
backups for immunogenicity and stability for commercial development. 2) Define the immunologic and toxicologic
GC biomarkers of INX200. These biomarkers will be measured and compared to the definitive pharmacological
signatures known to be specifically altered by systemic exposure to GC. INX200-dependent modulation of
cytokines and induction of steroid-specific transcripts will be assessed as immunologic and toxicity biomarkers,
respectively. 3) Conduct non-GLP Tox/PK/PD studies in cynomolgus monkeys in order to confirm safety and
guide the development of a subsequent IND-enabling GLP tox study. 4) Review and assess the regulatory path
to IND. The data generated in aims (1)-(3), in particular non-GLP non-human primate (NHP) studies, will be
reviewed to design (a) a single ascending dose Phase 1 trial in healthy volunteers, and (b) a multiple ascending
dose Phase 2 trial in GC-dependent asthma patients. Based on this clinical program outline, a GLP toxicology
study in NHP will be designed to support an IND.
The successful targeting of GC to the immune system with the sparing of non-hematopoietic toxicities, offers
a transformative advance in GC-based drugs for the treatment of severe, chronic inflammatory disease.
糖皮质激素(GC)是一类具有很强抗炎活性的药物。然而,剂量
项目成果
期刊论文数量(0)
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JAY L ROTHSTEIN其他文献
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{{ truncateString('JAY L ROTHSTEIN', 18)}}的其他基金
Immune cell targeting of corticosteroids transforms the treatment of severe, chronic inflammatory diseases
皮质类固醇的免疫细胞靶向改变了严重慢性炎症性疾病的治疗
- 批准号:
10435587 - 财政年份:2021
- 资助金额:
$ 99.38万 - 项目类别:
Immune cell targeting of corticosteroids transforms the treatment of severe, chronic inflammatory diseases
皮质类固醇的免疫细胞靶向改变了严重慢性炎症性疾病的治疗
- 批准号:
10324755 - 财政年份:2021
- 资助金额:
$ 99.38万 - 项目类别:
Targeting leukocyte metabolism to treat human autoimmune disease
靶向白细胞代谢治疗人类自身免疫性疾病
- 批准号:
9763441 - 财政年份:2018
- 资助金额:
$ 99.38万 - 项目类别:
Targeting the checkpoint regulator VISTA for treatment of inflammatory disease
靶向检查点调节因子 VISTA 治疗炎症性疾病
- 批准号:
9255938 - 财政年份:2017
- 资助金额:
$ 99.38万 - 项目类别:
Targeting the checkpoint regulator VISTA for treatment of inflammatory disease
靶向检查点调节因子 VISTA 治疗炎症性疾病
- 批准号:
9752441 - 财政年份:2017
- 资助金额:
$ 99.38万 - 项目类别:
Safe and effective anti CD154 antibodies for therapeutic intervention
用于治疗干预的安全有效的抗 CD154 抗体
- 批准号:
9202640 - 财政年份:2012
- 资助金额:
$ 99.38万 - 项目类别:
Safe and effective anti CD154 antibodies for therapeutic intervention
用于治疗干预的安全有效的抗 CD154 抗体
- 批准号:
9271146 - 财政年份:2012
- 资助金额:
$ 99.38万 - 项目类别:
EMZF-1--A NOVEL GENE REQUIRED FOR EMBRYONIC HEMATOPOIESIS
EMZF-1--胚胎造血所需的新基因
- 批准号:
6101895 - 财政年份:1999
- 资助金额:
$ 99.38万 - 项目类别:














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