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: 10625527
• 负责人: JAY L ROTHSTEIN
• 金额: $ 99.38万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625527
• 关键词: Address; Adrenal Cortex Hormones; Affinity; Anti-Inflammatory Agents; Antibodies; Antibody-drug conjugates; Asthma; Autoimmune Diseases; Award; Biological; Biological Markers; Biological Products; Black race; Budesonide; Cells; Chronic; Chronic Disease; Clinic; Clinical; Clinical Treatment; Confidential Information; Data; Development; Disease; Dose; Dose Limiting; Eligibility Determination; 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; Pharmacotherapy; Phase; Price; Process; Proteins; Request for Proposals; Risk; Risk Management; Running; Safety; Small Business Innovation Research Grant; Specificity; Steroids; Stress; Surveys; Testing; Therapeutic; Therapeutic Effect; Therapeutic Equivalency; Tissues; Toxic effect; Toxicology; Transcript; asthmatic; asthmatic patient; chronic inflammatory disease; clinical efficacy; commercialization; cytokine; design; disorder control; drug discovery; efficacy evaluation; healthy volunteer; immunogenicity; in vivo; lead candidate; manufacture; new therapeutic target; nonhuman primate; panacea; patient population; pharmacokinetics and pharmacodynamics; pharmacologic; 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。但是，剂量 由全身性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。这个直接的SBIR第2阶段提案请求支持小说 将GC送到免疫系统的治疗性，这将减少DLT并长期允许 GC在炎症治疗中的高剂量使用。 Immunext已确立了技术优点， 靶向抗体的，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对免疫系统的特定和直接靶向 FC-SiLent，完全人性化的免疫靶向mAb的抗体 - 药物结合物（ADC）通过A 可裂解的连接器到布德索德。重要的是，用INX200靶向GC会降低效力并降低 与游离GC相比，毒性。我们已经表明，INX200：1）用 造血室外的最小暴露量，2）利用免疫靶向的mAb本身 （未缀合）没有已知的免疫学活动，并且仅作为靶向剂而起作用，3）迅速 内部化允许对GC的强大有效吸收，从而提供GC的较高负载 免疫细胞，4）在治疗上等效于剂量的1/10，与PD相比，PD的时间更长。 自由GC，5）由于其特异性免疫而与游离GC相比，靶向活性最少，毒性降低 系统靶向6）适用于SC给药，7）是一种用于治疗GC-的有吸引力的治疗方法。 由于该患者人群的GC需要未满足的GC，依赖性哮喘。 该第2阶段应用的具体目的如下。 1）评估铅ADC INX200和多个 免疫原性和商业发展的稳定性的备份。 2）定义免疫和毒理学 INX200的GC生物标志物。将测量这些生物标志物并将其与确定的药理学进行比较 已知的签名是通过全身暴露于GC特异性改变的。 INX200依赖性调制 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志物， 分别。 3）在cynomolgus猴子中进行非GLP TOX/PK/PD研究，以确认安全性和 指导随后的成立GLP TOX研究的发展。 4）审查和评估监管路径 到印度。目标（1） - （3）中产生的数据，特别是非GLP非人类灵长类动物（NHP）研究 在健康志愿者中进行了审查（a）（a）一次升剂剂量1期试验，以及（b）多个上升 GC依赖性哮喘患者的剂量2期试验。基于此临床计划大纲，GLP毒理学 NHP的研究将设计为支持IND。 通过保留非脊髓毒素的毒性，将GC成功靶向免疫系统，提供 基于GC的药物的变革性进步，用于治疗严重的慢性炎性疾病。