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
• 负责人: JAY L ROTHSTEIN
• 金额: $ 99.09万
• 依托单位: IMMUNEXT, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-22 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10324755
• 关键词: Address; Adrenal Cortex Hormones; Affinity; Anti-Inflammatory Agents; Antibodies; Antibody-drug conjugates; Asthma; Autoimmune; Award; Biological; Biological Markers; Budesonide; Cells; Chronic; Chronic Disease; Cleaved cell; Clinic; Clinical; Clinical Treatment; Confidential Information; Data; Development; Disease; Dose; Dose-Limiting; Engineering; Exposure to; Glucocorticoids; Goals; Hand; Hematopoietic; Human; Immune; Immune Targeting; Immune system; Immunologics; In Vitro; Inflammation; Inflammatory; Laboratories; Lead; Lung; Macaca fascicularis; Maximum Tolerated Dose; Measurable; Measures; Modeling; Monoclonal Antibodies; Mus; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Price; Process; Proteins; Request for Proposals; Risk; Risk Management; Rivers; Running; Safety; Small Business Innovation Research Grant; Specificity; Steroids; Stress; Surveys; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Toxic effect; Toxicology; Transcript; asthmatic; asthmatic patient; base; chronic inflammatory disease; clinical efficacy; cytokine; design; drug discovery; efficacy evaluation; healthy volunteer; immunogenicity; in vivo; lead candidate; new therapeutic target; nonhuman primate; panacea; patient population; pharmacokinetics and pharmacodynamics; phase I trial; phase II trial; prevent; programs; side effect; standard of care; targeted agent; targeted delivery; transcriptomics; uptake

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)是一类具有压倒性抗炎活性的药物。然而，剂量 全身性GC暴露引起的限制毒性(DLT)阻止GC成为真正的灵丹妙药 炎症性疾病的管理。此直接SBIR第2阶段计划请求支持一项 靶向免疫系统的GC的治疗，这将减少DLT，并允许长期 大剂量应用糖皮质激素治疗炎症。ImmuNext已经确立了技术优势， 这种抗体靶向、免疫特异性类固醇的可行性、概念证明和商业潜力 共轭。我们已经通过INX200实现了GC对免疫系统的特异性和直接靶向 Fc沉默的全人化免疫靶向单抗的抗体-药物结合物(ADC) 布地奈德的可切割连接物。重要的是，以INX200为目标的GC会产生更好的效力并降低 毒性与游离GC相比。我们已经证明，INX200：1)广泛地以免疫系统为靶点 最小限度地暴露在造血室外，2)利用免疫靶向单抗本身 (未结合)没有已知的免疫活性，仅作为靶向试剂，3)快速 内部化，允许稳健和有效地吸收GC，从而提供更好的GC负载到 免疫细胞，4)在治疗上相当于十分之一的剂量，与之相比，PD显著延长 游离型GC，5)由于其特异性免疫，与游离型GC相比，脱靶活性最小，毒性更低 系统靶向，6)适合SC给药，7)是治疗GC的一种有吸引力的疗法- 依赖型哮喘，因为这一患者群体中的GC需求未得到满足。 这一第二阶段应用的具体目标如下。1)评估领先的ADC INX200和多个 为商业开发提供免疫原性和稳定性的支持。2)确定免疫学和毒理学 INX200的GC生物标志物。这些生物标志物将被测量并与权威的药理学 已知的签名是通过全身暴露于GC而特别改变的。依赖于INX200的调制 细胞因子和类固醇特异性转录本的诱导将被评估为免疫学和毒性生物标记物， 分别进行了分析。3)在食蟹猴身上进行非GLP的Tox/PK/PD研究，以确认安全性和 指导后续支持IND的GLP毒性研究的发展。4)审查和评估监管路径 到Ind.AIMS(1)-(3)，特别是非GLP非人灵长类(NHP)研究中产生的数据将是 审查以设计(A)健康志愿者的单次递增剂量1期试验，以及(B)多次递增试验 GC依赖型哮喘患者的剂量第二阶段试验。根据这一临床计划大纲，GLP毒理学 在NHP的学习将被设计为支持IND。 GC靶向免疫系统的成功，避免了非造血毒性，提供了 基于GC的药物治疗严重慢性炎症性疾病的变革性进展。