Immune cell targeting of corticosteroids transforms the treatment of severe, chronic inflammatory diseases

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）阻止了GC成为治疗糖尿病的真正灵丹妙药。 炎症性疾病的管理。该直接SBIR第2阶段提案要求支持一种新的 靶向将GC递送至免疫系统的治疗剂，这将减少DLT并允许长期 以及高剂量GC在炎症治疗中的应用。ImmuNext已经建立了技术优势， 这种抗体靶向的免疫特异性类固醇的可行性、概念证明和商业潜力 共轭我们已经使用INX 200实现了GC对免疫系统的特异性和直接靶向作用，INX 200是一种 Fc沉默的、完全人源化的免疫靶向mAb的抗体-药物缀合物（ADC），其通过免疫缀合物缀合。 布地奈德的可裂解接头。重要的是，用INX 200靶向GC导致上级效力和降低的 与游离GC相比，我们已经证明INX 200：1）广泛靶向免疫系统， 最小限度地暴露于造血区室之外，2）利用免疫靶向mAb， （未缀合的）不具有已知的免疫活性，仅作为靶向剂，3）快速 内化允许GC的稳健和有效摄取，从而提供GC向细胞内的上级负载。 免疫细胞，4）在1/10剂量下治疗等效，并且与免疫细胞相比具有显著更长的PD。 游离GC，5）由于其特异性免疫活性，与游离GC相比具有最小的脱靶活性和降低的毒性。 系统靶向，6）适用于SC给药，7）是治疗GC-1的有吸引力的治疗剂。 依赖性哮喘，因为该患者人群中GC需求未得到满足。 第二阶段申请的具体目的如下。1)评估导线ADC INX 200和多个 用于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 INX 200的GC生物标志物。将测量这些生物标志物，并与确定的药理学指标进行比较。 已知通过全身暴露于GC而特异性改变的特征。INX 200依赖性调节 细胞因子和类固醇特异性转录物的诱导将作为免疫学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IND使能GLP毒性研究的开发。4)审查和评估监管路径 目的（1）-（3）中生成的数据，特别是非GLP非人灵长类动物（NHP）研究，将 审查以设计（a）在健康志愿者中进行的单次给药剂量递增1期试验，和（B）多次给药剂量递增 在GC依赖性哮喘患者中进行的剂量II期试验。根据本临床项目概述，GLP毒理学 NHP研究的设计将支持IND。 GC成功地靶向免疫系统而不产生非造血毒性， 这是基于GC的药物在治疗严重慢性炎症性疾病方面的革命性进展。

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.