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：
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
项目类别：
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

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 暴露引起的限制性毒性 (DLT) 阻碍了 GC 成为真正的灵丹妙药。炎症性疾病的管理。该直接 SBIR 第 2 阶段提案请求支持小说靶向将 GC 递送至免疫系统的治疗方法，这将减少 DLT 并实现长期治疗以及高剂量使用GC治疗炎症。 ImmuNext 建立了技术优势，这种抗体靶向、免疫特异性类固醇的可行性、概念验证和商业潜力共轭。我们已经通过 INX200 实现了 GC 特异性、直接靶向免疫系统，INX200 是一种 Fc 沉默、完全人源化免疫靶向 mAb 的抗体药物偶联物 (ADC)，通过布地奈德的可切割接头。重要的是，使用 INX200 靶向 GC 可产生卓越的效力并降低与游离GC相比的毒性。我们已经证明 INX200：1) 广泛针对免疫系统造血室外的暴露最小化，2) 利用自身的免疫靶向单克隆抗体（未结合的）不具有已知的免疫活性，仅作为靶向剂，3）快速内化允许 GC 的稳健和高效吸收，从而提供 GC 的卓越加载免疫细胞，4) 在 1/10 剂量下具有治疗等效性，并且与与游离 GC 相比，游离 GC，5) 由于其特异性免疫，具有最小的脱靶活性和较低的毒性系统靶向，6) 适合 SC 给药，7) 是治疗 GC- 的一种有吸引力的治疗方法依赖性哮喘，因为该患者群体中 GC 需求未得到满足。第二阶段申请的具体目标如下。 1) 评估领先的 ADC INX200 和多个商业开发的免疫原性和稳定性的备份。 2) 定义免疫学和毒理学 INX200 的 GC 生物标志物。这些生物标志物将被测量并与确定的药理学进行比较已知特征会因全身暴露于 GC 而发生特别改变。 INX200 相关调制细胞因子和类固醇特异性转录物的诱导将作为免疫和毒性生物标志物进行评估，分别。 3) 在食蟹猴中进行非 GLP Tox/PK/PD 研究，以确认安全性和指导后续支持 IND 的 GLP 毒物研究的开发。 4）审查和评估监管路径至 IND。目标 (1)-(3) 中生成的数据，特别是非 GLP 非人类灵长类动物 (NHP) 研究，将审查设计（a）在健康志愿者中进行单次递增剂量的 1 期试验，以及（b）多次递增剂量 GC 依赖性哮喘患者的剂量 2 期试验。根据该临床计划大纲，GLP 毒理学 NHP 的研究旨在支持 IND。 GC 成功靶向免疫系统，且不产生非造血毒性，提供了用于治疗严重慢性炎症性疾病的基于 GC 的药物的革命性进展。